LV13669B - Alpha ketoamide compounds as cysteine protease inhibitors - Google Patents

Alpha ketoamide compounds as cysteine protease inhibitors Download PDF

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LV13669B
LV13669B LVP-07-121A LV070121A LV13669B LV 13669 B LV13669 B LV 13669B LV 070121 A LV070121 A LV 070121A LV 13669 B LV13669 B LV 13669B
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ylmethanesulfonylmethyl
alkyl
hydrogen
pyridin
haloalkyl
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LVP-07-121A
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Michael Graupe
John O Link
Michael G Roepel
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Applera Corp
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Abstract

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Description

Alfa ketoamīdu savienojumi ka cisterna proteāzes inhibitoriAlpha ketoamide compounds are tank protease inhibitors

Atsauces uz saistītiem pieteikumiem [0001] Šis patentapieteikums pretendē uz Provizoriskā patentpieteikuma Nr. 60/663,970, iesniegta 2005.gada 21.martā un Provizoriskā patentpieteikuma Nr. 60/684,623, iesniegta 2005.gada 24.maijā priekšrocībām, abi patentpieteikumi ir šeit iekļauti ar atsauci.References to Related Applications [0001] This patent application claims a prior art patent application no. 60 / 663,970, filed March 21, 2005; 60 / 684,623, filed May 24, 2005, both patent applications are incorporated herein by reference.

Pieteikums izgudrojuma tiesību saņemšanai federāli Atbalstīto pētījumu vai izstrādes ietvarosApplication for Acquisition of Invention under Federal Supported Research or Development

[0002] NAV PIEMĒROJAMS[0002] NOT APPLICABLE

Atsauce uz kompaktdiskā iesniegto "secības sarakstu”, tabulu vai datorprogrammas saraksta pielikumu, kas iesniegts kompaktdiskāReference to " Sequence List ”, Table or Computer Program Attachment Attached to CD

[0003] NAV PIEMĒROJAMS[0003] NOT APPLICABLE

Izgudrojuma nozare [0004] Šī izgudrojuma priekšmets ir savienojumi, kas ir cisteīna prot.eāžu inhibitori, it īpaši katepsīni B, K, L, F un S, un tāpēc šie savienojumi ir lietderīgi, ārstējot slimības, kurās šīs proteāzes ir starpnieces. Šī izgudrojuma priekšmets ir .arī farmaceitiskas kompozīcijas, kas satur šos savienojumus, un to pagatavošanas procesi.BACKGROUND OF THE INVENTION The present invention relates to compounds which are cysteine protease inhibitors, in particular cathepsins B, K, L, F and S, and therefore are useful in the treatment of diseases in which these proteases are mediators. The subject of this invention is the pharmaceutical compositions containing these compounds and their preparation processes.

Esošais nozares stāvoklis [0005] Cisteīna proteāzes ir peptidāžu grupa, kas raksturojama ar cisteīna palieku klātbūtni enzīma katalītiskajā zonā. Cisteīna proteāzes saistāmas ar proteīnu normālu sadalīšanu un pārstrādi. Bet anomālai cisteīna proteāžu aktivitātei, piemēram, palielinātas parādīšanās vai aktivācijas‘rezultātā, var būt patoloģiskas sekas. Šajā aspektā dažas cisteīna proteāzes saistāmas ar vairākiem slimības stāvokļiem, ieskaitot artrītu, muskuļu distrofiju, iekaisumu, audzēju invāziju, glomerulonefrītu, malāriju, periodontālo slimību, metahromātīsko leikodistrofiju un citas. Tā, piemēram, palielināti katepsīna B · līmeņi un enzīma sadalīšanas izmaiņas konstatētas audzējos, un minētais ļauj pieņemt enzīma lomu audzēju invāzijā un metastāžu veidošanā. Bez tam, anomālā katepsīna B aktivitāte iesaistīta tādos slimības stāvokļos kā reimatoīdais atrīts, osteoartrīts, Pneumocystis carinii, asais pankreatīts, elpošanas ceļu iekaisums un kaulu un locītavu traucējumi.Existing state of the art Cysteine proteases are a group of peptidases characterized by the presence of cysteine residues in the catalytic zone of the enzyme. Cysteine proteases are associated with normal protein digestion and processing. But abnormal cysteine protease activity, such as increased appearance or activation, may have pathological effects. In this regard, some cysteine proteases are associated with a number of conditions including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromate leukodistrophy and others. For example, increased levels of cathepsin B · and changes in enzyme degradation have been found in tumors, and this allows the role of the enzyme in tumor invasion and metastasis. In addition, abnormal cathepsin B activity is involved in conditions such as rheumatoid arthritis, osteoarthritis, Pneumocystis carinii, pancreatitis, inflammation of the respiratory tract and bone and joint disorders.

[0006] Ievērojama katepsīna K parādīšanās osteoklastos un ar osteoklastiem saistītajās daudzu kodolu šūnās, kā arī tā liela kolagēnolītiskā aktivitāte ļauj pieņemt, ka enzīms ir iesaistīts ar osteoklastiem saistītajā kaulu resorbcijā un tātad kaulu anomālijās, kādas sastopamas osteoporozes gadījumā. Bez tam katepsīna K parādīšanās plaušās un tā elastinolītiskā aktivitāte ļauj pieņemt, ka enzīmam ir kāda loma arī plaušu traucējumos.Significant emergence of cathepsin K in osteoclasts and osteoclast-associated nuclei, as well as its high collagenolytic activity, suggests that the enzyme is involved in osteoclast-associated bone resorption and hence bone abnormalities that occur in osteoporosis. In addition, the appearance of cathepsin K in the lungs and its elastinolytic activity suggest that the enzyme also plays a role in lung disorders.

[0007] Katepsīns L ir iesaistīts normālā lizosomālajā proteolīzē, kā arī vairākos slimības stāvokļos, ieskaitot, bet ar to neierobežojoties, melanomas metastāžu veidošanos. Katepsīns S ir iesaistīts Alcheimera slimībā un noteiktos autoimūnos traucējumos, ieskaitot, bet ar to neierobežojoties, pusaudžu diabēta sākuma stāvokli, izkliedēto sklerozi, pemphigus vulgaris, Greiva slimību, mya$thenia grāvis, sistēmisku iupus erythemotasus, reimatoīdu artrītu, neiropātiskas sāpes un Hašimoto tiroidītu. Bez tam. katepsīns S iesaistīts alerģiskos traucējumos, ieskaitot, bet ar to neierobežojoties, astmu; un aloģenās imūnās reakcijās, ieskaitot, bet arto neierobežojoties, orgānu transplantu vai audu transplantu atgrūšanu.Cathepsin L is involved in normal lysosomal proteolysis, as well as in a number of disease states including, but not limited to, melanoma metastasis. Cathepsin S is involved in Alzheimer's disease and certain autoimmune disorders, including but not limited to adolescent diabetes, the onset of sclerosis, pemphigus vulgaris, Greiva disease, mya thenia ditch, systemic iupus erythematosus, rheumatoid arthritis, neuropathic pain and Hashimoto thyroiditis. Furthermore. Cathepsin S is involved in allergic disorders, including but not limited to asthma; and allogeneic immune responses including, but not limited to, organ transplant or tissue transplant rejection.

[0008] Ņemot vērā vairākas slimības, kuru gadījumā ir konstatēts, ka cisterna proteāzes aktivitātes pieaugums veicina patoloģiju un/vai slimības sīmptomatoloģiju, molekulas, kuras inhibē šo enzīmu grupas aktivitāti, it īpaši molekulas, kas inhibē katepsīnu B, K, L, F un/vai S, var būt noderīgas kā terapeitiski līdzekļi.[0008] In view of a number of diseases in which the increase in the protease activity of the tank is found to contribute to pathology and / or disease typology, molecules that inhibit the activity of this enzyme group, in particular, molecules that inhibit cathepsin B, K, L, F and \ t / or S may be useful as therapeutic agents.

Izgudrojuma kopsavilkums [0009] Pirmajā aspektā šī izgudrojuma priekšmets ir savienojums ar formulu (I):SUMMARY OF THE INVENTION In a first aspect, the subject of the invention is a compound of formula (I):

¥ H P i I b l¥ H P i I b l

R ļ -N H R5 h O R‘ kur: R1 ir ūdeņradis vai alkilgrupa; R2 ir cikloalkilgrupa, cikloafkilalkilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa, kas neobligāti ir aizvietota ar vienu vai diviem aizvietotājiem, neatkarīgi izvēlētiem no alkilgrupas, alkoksigrupas vai halogēna; R3 ir ūdeņradis, alkilgrupa vai alkoksialkilgrupa; R4 ir alkilgrupa; vai R3 un R4 kopā ar oglekļa atomu, ar ko tie savienoti, veido cikloalkilēnu, kas neobligāti aizvietots ar vienu līdz četriem fluora atomiem, vai heterocikloalkilēnu, kas neobligāti aizvietots ar alkilgrupu, alkoksialkilgrupu, hidroksialkilgrupu, acilgrupu, cikloalkilgrupu, cikioalkilalkilgrupu vai haloalkilgrupu; R5 ir alkilgrupa, haloaikilgrupa, kas neobligāti aizvietota ar cikloalkilgrupu, arilgrupu, heteroarilģrupu vai heterocikloalkilgrupu, cikloalkilalkilgruu, aralkilgrupu, heteroaralkīlgrupu, heterocikloalkilalkilgrupu, -(alkilēn)- X-R9 (kur X ir -O-, -S-, -SO-, -S02-, -CONH-, -NHCO- vai -NHS02- un R9 ir alkilgrupa, haloaikilgrupa, cikloalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgtrupa, heteroaralkilgrupa, heterocikloalkilgrupa vai heterocikloalkilalkilgrupa) vai -(alkilēn)-X1-(haloalkilēn)-R10 (kurX1 ir-O-, -S-, -SO-, -S02-, -CONH-, -NHCO- vai -NHS02- un R10 ir cikloalkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa), kur aromātiskais vai alicikliskais gredzens R5 neobligāti ir aizvietots ar vienu, diviem vai trim Ra, kas neatkarīgi ir izvēlēti no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas, ciāngrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas; vai neobligāti aizvietots ar vienu vai diviem Rb, kas neatkarīgi izvēlēti no ūdeņraža, alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēts no hidroksialkilgrupas, alkoksialkilgrupas, aminoalkilgrupas, arilgrupas, heteroarilgrupas, aralkifgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgrupas, heterocikloalkilgrupas, heterocikloalkilalkilgrupas, acilgrupas, acilafkilgrupas, ariloksikarbonilgrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, cikloalkiloksikarbonilgrupas, ariloksigrupas, heteroariloksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonilgrupas vai -SO2R11 (kurR11 ir alkilgrupa, cikloalkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa); un, turklāt, kur aromātiskais vai alicikliskais gredzens Rc neobligāti ir aizvietots ar vienu, diviem vai trim Rd, kas neatkarīgi izvēlēti no alkilgrupas, alkilsulfonilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas vai halogēna; R6 ir haloalkilgrupa; R7 ir ūdeņradis, alkilgrupa vai haloalkilgrupa; un R8 ir ūdeņradis, alkilgrupa, haloalkilgrupa, cikloalkilgrupa, arilgrupa, heteroarilgrupa, heterocikloalkilgrupa, kas pievienota ar oglekļa atoma starpniecību, kur aromātiskais vai alicikliskais gredzens R8 neobligāti aizvietots ar vienu, diviem vai trim Re, kas neatkarīgi izvēlēti no alkilgrupas, halogēna, haloalkilgrupas, hidroksilgrupas, alkoksigrupas, haloalkoksigrupas, alkilkarbonilgrupas, alkoksikarbonilgrupas, karboksilgrupas, ciānogrupas, alkilsulfonilgrupas, aikilsulfonilaminogrupas, aminokarbonilgrupas vai aminosulfonilgrupas; vai tā farmaceitiski pieņemami sāļi.R 1 -N H R 5 h O R 'wherein: R 1 is hydrogen or alkyl; R 2 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl or heteroaralkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy or halogen; R3 is hydrogen, alkyl or alkoxyalkyl; R4 is alkyl; or R3 and R4 together with the carbon atom to which they are attached form cycloalkylene optionally substituted with one to four fluorine atoms, or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl or haloalkyl; R5 is alkyl, haloalkyl optionally substituted with cycloalkyl, aryl, heteroaryl or heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, - (alkylene) - X-R9 (wherein X is -O-, -S-, -SO-, -SO 2 -, -CONH-, -NHCO- or -NHSO 2 - and R 9 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroarylgroup, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl) or - (alkylene) -X 1 - (haloalkylene) - R10 (where X1 is -O-, -S-, -SO-, -SO2-, -CONH-, -NHCO- or -NHSO2- and R10 is cycloalkyl, aryl, heteroaryl or heterocycloalkyl) wherein the aromatic or alicyclic ring R5 is optional is substituted by one, two, or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano, halogen, carboxyl or alkoxycarbonyl; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaralkyl , cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acilafkilgrupas, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, cikloalkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -SO2R11 (kurR11 alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and furthermore, wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three Rd independently selected from alkyl, alkylsulfonyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen; R6 is haloalkyl; R7 is hydrogen, alkyl or haloalkyl; and R8 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl attached via a carbon atom, wherein the aromatic or alicyclic ring R8 is optionally substituted with one, two or three Re independently selected from alkyl, halo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, alkylsulfonyl, alkylsulfonylamino, aminocarbonyl or aminosulfonyl; or a pharmaceutically acceptable salt thereof.

[0010] Otrajā aspektā šī izgudrojuma priekšmets ir farmaceitiska kompozīcija, kas satur savienojumu ar formulu (!) vai šī savienojuma farmaceitiski pieņemamu sāli, sajaucot ar vienu vai vairākām piemērotām piidvielām.In a second aspect, the subject of the invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

[0011] Trešajā aspektā šī izgudrojuma priekšmets ir paņēmiens slimības ārstēšanai dzīvniekā, gadījumā, ja slimībā iesaistītas cisteīna proteāzes, it īpaši katepsīns S, turklāt piemērojot šo paņēmienu, dzīvniekam ievada farmaceitisku kompozīciju, kas satur savienojuma ar formulu (I) efektīvu daudzumu vai tā farmaceitiski pieņemamu sāli, sajaucot ar vienu vai vairākām piidvielām.In a third aspect, the subject of the invention is a method for treating an animal in an animal in which the disease involves cysteine proteases, in particular cathepsin S, furthermore, by administering the method, administering to the animal a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof. acceptable salt by mixing with one or more fatty acids.

[0012] Ceturtajā aspektā šī izgudrojuma priekšmets ir savienojuma ar formulu (I) pagatavošanas paņēmieni.In a fourth aspect, the subject of the present invention is a process for preparing a compound of formula (I).

[0013] Piektajā aspektā šī izgudrojuma priekšmets ir ārstēšanas paņēmiens, kad pacientu pakļauj terapijai un šī terapija izraisa imūno reakciju pacientā, galvenokārt kaitīgu imūno reakciju, turklāt pacientam ievada savienojumu ar formulu (I) vai tā farmaceitiski pieņemamu sāli. Imūnās reakcijas starpnieces ir galvenokārt MHC II grupas molekulas. Savienojumu, kas ir šī izgudrojuma 4 priekšmets, var ievadīt pirms vai pēc terapijas vai vienlaikus ar to. Labāk, ja terapija satur ārstēšanu ar bioloģisku preparātu. Labāk, ja terapija satur ārstēšanu ar mazu molekulu.In a fifth aspect, the subject of the invention is a method of treatment wherein a patient is subjected to treatment and this treatment induces an immune response in a patient, primarily a harmful immune response, and the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof. Immune response mediators are mainly MHC Group II molecules. The subject matter of this invention 4 may be administered before or after therapy or concurrently therewith. It is better to treat the treatment with a biological treatment. It is better if the therapy contains a small molecule treatment.

[0014] Labāk, ja bioloģiskais preparāts ir proteīns, labāk antiviela, vislabāk monoklonālā antiviefa. Vislabāk bioloģiskais preparāts ir Remicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®, Epogen®, Enbrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Myobloc®, Aldurazyme®, Veduma®, Interferon aipha, Humira®, Aranesp®, Zevalin®vai OKT3.It is preferred that the biological preparation is a protein, preferably an antibody, preferably a monoclonal antivief. The best biological agent is Remicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®, Epogen®, Enbrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Myobloc®, Aldurazyme® , Veduma®, Interferon Aipha, Humira®, Aranesp®, Zevalin® or OKT3.

[0015] Labāk, ja ārstēšana satur heparīna, mazas molekulārās masas heparīna, prokaīnamīda vai hidralazīna izmantošanu.Preferably, the treatment comprises the use of heparin, low molecular weight heparin, procaineamide or hydralazine.

[0016] Sestajā aspektā šī izgudrojuma priekšmets ir paņēmiens imūnās reakcijas ārstēšanai dzīvniekā, ja šī reakcija tika izraisīta, bioloģisku preparātu ievadot dzīvniekam, pielietojot paņēmienu, un dzīvniekam, kam vajadzīga šī ārstēšana, ievada savienojuma ar formulu (I) vai tā farmaceitiski pieņēmama sāls efektīvu daudzumu.In a sixth aspect, the subject of the present invention is a method of treating an immune response in an animal when said reaction is caused by administering a biological preparation to an animal using a method, and administering to the animal in need of such treatment an effective compound of formula (I) or a pharmaceutically acceptable salt thereof. quantity.

[0017] Septītajā aspektā šī izgudrojuma priekšmets ir paņēmiens bioloģiskā preparāta klīniskā izmēģinājuma veikšanai, kuru pielietojot indivīdam, kas piedalās klīniskajā izmēģinājuma, ievada savienojumu ar formulu (I) vai tā farmaceitiski pieņemamu sāli kopā ar bioloģisko līdzekli.In a seventh aspect, the subject of the present invention is a method of conducting a clinical trial of a biological preparation administered to a subject participating in a clinical trial to administer a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a biological agent.

[0018] Astotāja aspektā šī izgudrojuma priekšmets ir profilaktiskās ārstēšanas paņēmiens, ja pacientu ārstē ar bioloģisko preparātu kopā ar savienojumu ar formulu (I) vai tā farmaceitiski pieņemamu sāli, ārstējot bioloģiskā preparāta izraisītu imūnu reakciju pacientā.In the aspect of the inventor, the subject of the invention is a method of prophylactic treatment when a patient is treated with a biological preparation in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a biological agent-induced immune response in a patient.

[0019] Devītajā aspektā šī izgudrojuma priekšmets ir paņēmiens bioloģiska līdzekļa efektivitātes samazināšanās noteikšanai dzīvniekā sakarā ar bioloģiskā preparāta izraisīto imūno reakciju, turklāt bioloģisko preparātu dzīvniekam ievada savienojuma ar formulu (I) vai tā farmaceitiski pieņemama sāls klātbūtnē un bez tā.In a ninth aspect, the subject of the present invention is a method for detecting a decrease in the efficacy of a biological agent in an animal due to an immune response induced by a biological preparation, wherein the biological preparation is administered to the animal in the presence and absence of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] Desmitajā aspektā šī izgudrojuma priekšmets ir paņēmiens bioloģiskā preparāta efektivitātes uzlabošanai dzīvniekā, turklāt bioloģisko preparātu dzīvniekam ievada kopā ar savienojumu ar formulu (I) vai tā farmaceitiski pieņemamu sāli.In a tenth aspect, the subject of the invention is a method of improving the efficacy of a biological preparation in an animal, and the biological preparation is administered to the animal in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] Vienpadsmitajā aspektā šī izgudrojuma priekšmets ir savienojuma ar formulu (I) vai tā farmaceitiski pieņemama sāls izmantošana medikamenta pagatavošanai. Labāk, ja medikaments paredzēts tādas slimības ārstēšanai, kur slimības starpnieks ir katepsīns S.In the eleventh aspect, the object of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament. It is better for the medicine to treat a disease where the disease mediator is cathepsin S.

[0022] Divpadsmitajā aspektā šī izgudrojuma priekšmets ir savienojuma ar formulu (I) vai tā farmaceitiski pieņemama sāls izmantošana medikamenta pagatavošanai, medikamentu paredzot izmantošanai kopā ar bioloģisko preparātu kombinētā terapijā, kur savienojums, kas ir šī izgudrojuma 5 5 LV 13669 priekšmets, ārstē bioloģiskā preparāta izraisītu imūnu reakciju. Labāk, ja savienojumu(s), kas ir šī izgudrojuma priekšmets, ievada pirms bioloģiskā preparāta ievadīšanas. Labāk, ja savienojumu(s), kas ir šī izgudrojuma priekšmets, ievada kopā ar bioloģisko preparātu. Labāk, ja savienojumu(s), kas ir šī izgudrojuma priekšmets, ievada pēc bioloģiskā preparāta ievadīšanas.In a twelfth aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with a biological preparation in combination therapy wherein the compound of the present invention is treated with a biological preparation. immune response. It is preferred that the compound (s) of the present invention be administered prior to administration of the biological preparation. It is preferable that the compound (s) which are the subject of the present invention be administered with the biological preparation. It is preferred that the compound (s) of the present invention be administered after the administration of the biological preparation.

Detalizētais izgudrojuma aprakstsDetailed description of the invention

Definīcijas: [0023] Ja nav noteikts citādi, šādi aprakstā un pretenzijās lietoti termini ir derfinēti šī pieteikuma mērķiem un tiem ir šādas nozīmes.Definitions: Unless otherwise stated, the terms used in the description and claims are refined for the purposes of this application and have the following meanings.

[0024] “Aliciklisks” nozīmē funkcionālu grupu, kurā oglekļa atomi sakārtoti slēgtās nearomātiskās gredzena struktūrās, piemēram, cikloalkila un heterocikloalkila gredzenos tā, kā noteikts šeit."Alicyclic" means a functional group in which carbon atoms are arranged in closed non-aromatic ring structures such as cycloalkyl and heterocycloalkyl as defined herein.

[0025] "Aikilgrupa" pati par sevi nozīmē taisnu vai sazarotu, piesātinātu alifāiisku atlikumu, kas satur vienu līdz astoņus oglekja atomus, ja nav norādīts citādi, piemēram, aikilgrupa satur metilgrupu, etiigrupu, izopropilgrupu, butilgrupu, sekbutilgrupu, izobutilgrupu, tercbutilgrupu un tamlīdzīgi.&Quot; Time Group " by itself means a straight or branched, saturated aliphatic residue containing from one to eight carbon atoms unless otherwise indicated, such as alkyl containing methyl, ethynyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0026] "Alkilēngrupa", ja nav norādīts citādi, nozīmē taisnu vai sazarotu, piesātinātu alifāiisku divvērtīgu atlikumu ar vienu līdz sešiem oglekja atomiem, piemēram, metilēngrupu (-CH2-), etilēngrupu (-CH2CH2-), trimetilēngrupu (-CH2CH2CH2-), tetrametilēngrupu (-CH2CH2CH2CH2-) 2-metiitetra-metilēngrupu (-CH2CH(CH3)CH2CH2-), pentametilēngrupu (-CH2CH2GH2CH2CH2-) un tamlīdzīgi.&Quot; Alkylene ", unless otherwise indicated, means a straight or branched, saturated aliphatic bivalent residue of one to six carbon atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2- ), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -) 2-methylethylmethylene (-CH 2 CH (CH 3) CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 GH 2 CH 2 CH 2 -) and the like.

[0027] "Alkilsulfonilgrupa" nozīmē -S02R atlikumu, kur R ir šeit definētā aikilgrupa, piemēram, metilsulfonilgrupa, etiisulfonilgrupa un tamlīdzīgi.&Quot; Alkylsulfonyl " means a -SO2R residue, wherein R is an alkyl group, as defined herein, such as methylsulfonyl, ethysulfonyl, and the like.

[0028] "Alkilsulfonilaminogrupa" nozīmē -NHS02R atlikumu, kur R ir šeit definētā aikilgrupa, piemēram, metilsulfonilaminogrupa, etilsulfonilaminogrupa un tamlīdzīgi.&Quot; Alkylsulfonylamino " means a residue of -NHSO2R wherein R is alkyl as defined herein, such as methylsulfonylamino, ethylsulfonylamino, and the like.

[0029] "Alkoksigrupa" nozīmē -OR atlikumu, kur R ir šeit definētā aikilgrupa, piemēram, metoksigrupa, etoksigrupa un tamlīdzīgi.&Quot; alkoxy group " means -OR, where R is alkyl as defined herein, such as methoxy, ethoxy and the like.

[0030] " Alkoksialkilgrupa" ir lineārs vienvērtīgs ogļūdeņraža atlikums ar vienu līdz sešiem oglekļa atomiem vai sazarots vienvērtīgs ogļūdeņraža atlikums ar trim līdz sešiem oglekļa atomiem, kas aizvietoti vismaz ar vienu alkoksigrupu, labāk vienu vai divām alkoksigrupām kā definēts iepriekš, piemēram, 2-metoksi-etilgrupu, 1-, 2-vai 3-metoksipropilgrupu, 2-etoksietilgrupu un tamlīdzīgi.&Quot; Alkoxyalkyl " is a linear equal hydrocarbon residue with one to six carbon atoms or a branched, homogenous hydrocarbon residue with three to six carbon atoms substituted by at least one alkoxy group, preferably one or two alkoxy groups as defined above, e.g., 2-methoxyethyl, 1-, 2-or 3-methoxypropyl, 2-ethoxyethyl and the like.

[0031] "Alkoksikarbonilgrupa".nozīmē -C(0)OR atlikumu, R ir iepriekš definētā aikilgrupa, piemēram, metoksikarbonilgrupa, etoksikarbonilgrupa un tamlīdzīgi. 6 [0032] "Aminoalkilgrupa" ir lineārs vienvērtīgs ogļūdeņraža atlikums ar vienu līdz sešiem oglekļa atomiem vai sazarots vienvērtīgs ogļūdeņraža atlikums ar trim līdz sešiem oglekļa atomiem, kas aizvietoti vismaz ar vienu, labāk ar vienu vai divām -NRR' grupām, kur R ir ūdeņradis, afkilgrupa, acilgrupa, hidroksialkilgrupa, alkoksialkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa vai heterocikloalkilalkilgrupa un R’ ir ūdeņradis, alkilgrupa, hidroksialkilgrupa, alkoksialkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa, heterocikloalkilalkilgrupa, cikloalkilgrupa, cīkloalkilalkilgrupa, aminolarbonilgrupa vai aminosulfonilgrupa kā definēts šeit, piemēram, aminometilgrupa, metilamīnoetilgrupa, dimetilaminoetīlgrupa, 1,3-diaminopropilgrupa, acetilaminopropilgrupa un tamlīdzīgi.&Quot; Alkoxycarbonyl " means a -C (O) OR residue, R is a predetermined alkyl group such as methoxycarbonyl, ethoxycarbonyl and the like. 6 " Aminoalkyl " is a linear equal hydrocarbon residue of one to six carbon atoms or a branched, homogenous hydrocarbon residue with three to six carbon atoms substituted by at least one, preferably one or two, -NRR 'groups, wherein R is hydrogen, afkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl and R 'is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminolarbonilgrupa or aminosulfonyl as defined here, for example, aminomethyl, metilamīnoetilgrupa, dimethylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl and the like.

[0033] " Acilgrupa" nozīmē -COR atlikumu, kur R ir ūdeņradis, alkilgrupa, haloalkilgrupa, cikloalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heteroaralkilgrupa vai heterocikloalkilgrupa kā definēts šeit, piemēram, formilgrupa, acetilarupa, trifluoracetilgrupa, benzoilgrupa, piperazin-1-ilkarboniigrupa un tamlīdzīgi. Ja R ir alkilgrupa, šajā pieteikumā ar to jāsaprot alkilkarbonilgrupa.&Quot; Acyl " means a COR residue wherein R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl as defined herein, e.g. When R is alkyl, it is understood to include alkylcarbonyl in this application.

[0034] " Acilalkilgrupa" ir lineārs vienvērtīgs ogļūdeņraža atlikums ar vienu līdz sešiem oglekļa atomiem vai sazarots vienvērtīgs,ogļūdeņraža atlikums ar trim līdz sešiem oglekļa atomiem, kas aizvietoti vismaz ar vienu, labāk vienu vai divām acilgrupām kā definēts šeit, piemēram, metilkarbonilmetilgrupu, benzoiletilgrupu, piperidin-1-ilkarbonilmetil-vai etilgrupu un tamlīdzīgi.&Quot; Acylalkyl " is a linear equal hydrocarbon residue of one to six carbon atoms or branched monovalent hydrocarbon with three to six carbon atoms substituted with at least one, preferably one or two, acyl groups as defined herein, e.g. -or-ethyl and the like.

[0035] "Aminokarbonilgrupa" nozīmē -CONRR' atlikumu, kur R un R’ ir neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, arilgrupas, aralkilgrupas, heteroarilgrupas, heteroaraīkilgrupas vai heterocikloalkilalkilgrupas vai R un R' kopā ar slāpekļa atomu, ar ko tās ir saistītas, veido heterocikloaminogrupu kā definēts šeit.&Quot; Aminocarbonyl " means a -CONRR 'residue wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaryl, or heterocycloalkylalkyl, or R and R 'together with the nitrogen atom to which they are attached form a heterocycloamino group as defined herein.

[0036] 'Aminosulfonilgrupa" nozīmē -SO2NRR' atlikumu, kur R un R' ir neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, arilgrupas, aralkilgrupas, heteroarilgrupas, heteroaraīkilgrupas vai heterocikloalkilalkilgrupas vai R un R' kopā ar slāpekļa atomu, ar ko tās ir saistītas, veido heterocikloaminogrupu kā definēts šeit.'Aminosulfonyl' " means a -SO2NRR 'residue wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaryl, or heterocycloalkylalkyl, or R and R 'together with the nitrogen atom to which they are attached form a heterocycloamino group as defined herein.

[0037] "Dzīvnieks" ietver cilvēkus, zīdītājus, kas nav cilvēki (piemēram, suņi, kaķi, truši, liellopi, zirgi, aitas, kazas, cūkas, brieži un tamlīdzīgi), un dzīvniekus, kas nav zīdītāji (piemēram putni un tamlīdzīgi).&Quot; Animal " includes non-human mammals (such as dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer and the like) and non-mammals (eg birds and the like).

[0038] "Aromātisks" nozīmē funkcionālu grupu, kuras oglekļa atomi veido nepiesātinātu gredzena sistēmu un visi atomi gredzena sistēmā ir sp2 hibridizēti un kopējais pi elektronu skaits vienāds ar4n+2.&Quot; Aromatic " means a functional group whose carbon atoms form an unsaturated ring system and all atoms in the ring system are sp2 hybridized and the total number of pi electrons equals 4n + 2.

[0039] "Arilgrupa" ir monocikliska vai sapludināta bicikliska gredzena sistēma, kas satur 6 līdz 10 oglekļa atomus, kur katrs gredzens ir aromātisks, piemēram, fenilgrupa vai naftilgrupa.&Quot; Aryl " is a monocyclic or fused bicyclic ring system containing 6 to 10 carbon atoms, each ring being aromatic, such as phenyl or naphthyl.

[0040] "Ariloksigrupa" nozīmē -O-R atlikumu, kur R ir arilgrupa ka definēts iepriekš, piemēram, fenoksigrupa, naftiloksigrupa un tamlīdzīgi.&Quot; Aryloxy " means -O-R, wherein R is aryl as defined above, for example, phenoxy, naphthyloxy, and the like.

[0041] "Ariloksikarbonilgrupa" nozīmē -C(0)OR atlikumu, kur R ir arilgrupa kā definēts iepriekš, piemēram, feniloksikarbonilgrupa, naftiloksikarbonilgrupa un tamlīdzīgi.&Quot; Aryloxycarbonyl " means a residue of -C (O) OR wherein R is aryl as defined above, for example, phenyloxycarbonyl, naphthyloxycarbonyl and the like.

[0042] "Aralkilgrupa" nozīmē -(alkilēn)-R atlikumu, kur R ir arilgrupa kā definēts iepriekš, piemēram, benzilgrupa, fenetilgrupa un tamlīdzīgi.&Quot; Aralkyl " means a - (alkylene) -R residue, wherein R is aryl as defined above, for example, benzyl, phenethyl and the like.

[0043] "Aralkiloksigrupa" nozīmē -OR atlikumu, kur R ir aralkilgrupa kā definēts iepriekš, piemēram, benziloksigrupa, fenetiloksigrupa un tamlīdzīgi.&Quot; Aralkyloxy " means -OR, wherein R is aralkyl as defined above, for example, benzyloxy, phenethyloxy and the like.

[0044] 'Aralkiloksikarbonilgrupa" nozīmē -C(0)OR atlikumu, kur R ir aralkilgrupa kā definēts iepriekš, piemēram, benziloksikarbonilgrupa, fenetiloksikarbonilgrupa un tamlīdzīgi.Aralkyloxycarbonyl " means a residue of -C (O) OR wherein R is aralkyl as defined above, for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like.

[0045] "Bioloģisks preparāts" nozīmē terapeitisku līdzekli, kas iegūts no dzīviem organismiem un paredzēts slimības ārstēšanai vai regulēšanai. Piemēri satur, bet ar minēto neierobežojoties, proteīnus (rekombinantos un no plazmas iegūtos), monoklonālas vai poliklonālas, humanizētas vai peļu antivielas, toksīnus, hormonus un tamlīdzīgi. Pašlaik bīloģiskie preparāti izmantojami dažādu slimību ārstēšanai, tādu kā vēzis, reimatoīdais artrīts un hemofīlija.&Quot; Biological Preparation " means a therapeutic agent obtained from living organisms for the treatment or regulation of the disease. Examples include, but are not limited to, proteins (recombinant and plasma derived), monoclonal or polyclonal, humanized or mouse antibodies, toxins, hormones, and the like. Currently, biotic preparations are used to treat various diseases such as cancer, rheumatoid arthritis and haemophilia.

[0046] "Karboksilgrupa” nozīmē -C(0)OH atlikumu.&Quot; Carboxyl " means a residue of -C (O) OH.

[0047] "Cikloalkilgrupa" nozīmē vienvērtīgu piesātinātu monocikiisku gredzenu, kas satur trīs līdz astoņus oglekļa atomus, piemēram, ciklopropilgrupu, ciklobutilgrupu, ciklopentilgrupu, crkloheksilgrupu un tamlīdzīgi.&Quot; Cycloalkyl " means a monovalent saturated monocyclic ring containing three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, crchexyl and the like.

[0048] "Cikloalkilalkilgrupa" nozīmē -(alkilēn)-R atlikumu, kurR ir cikloalkilgrupa kā definēts iepriekš, piemēram, cikiopropilmetilgrupa, ciklobutiietilgrupa, ciklobutilmetilgrupa un tamlīdzīgi.&Quot; Cycloalkylalkyl " means a - (alkylene) -R residue, wherein R is cycloalkyl as defined above, for example, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl and the like.

[0049] "Cikloalkiloksikarbonilgrupa" nozīmē -C(0)OR atlikumu, kur R ir cikloalkilgrupa kā definēts iepriekš, piemēram, ciklopropiloksikarbonilgrupa, ciklopentiloksikarbonilgrupa un tamlīdzīgi.&Quot; Cycloalkyloxycarbonyl " means a residue of -C (O) OR wherein R is cycloalkyl as defined above, for example cyclopropyloxycarbonyl, cyclopentyloxycarbonyl and the like.

[0050] "Cikloalkilēngrupa" nozīmē divvērtīgu piesātinātu monocikiisku gredzenu, kas satur trīs līdz astoņus gredzena oglekļa atomus. Piemēram, gadījums, kurā “R3 un R4 kopā ar oglekļa.atomu, pie kura pievienoti abi R1 un R2, veido cikloalkilēngrupu”, satur, bet ar minēto neierobežojoties, sekojošo:&Quot; Cycloalkylene " means a bivalent saturated monocyclic ring containing three to eight ring carbon atoms. For example, a case where "R3 and R4, together with the carbon atom to which both R1 and R2 are attached, form a cycloalkylene group", but without being bound by the following:

un tamlīdzīgi.and the like.

[0051] "Slimība” konkrēti satur jebkuru dzīvnieka vai tā daļas neveselīgu stāvokli un satur neveselīgu stāvoklī, kuru varētu izraisīt vai kurš varētu būt saistīts ar medicīnisku vai veterināru terapiju, ko pielietoja šim dzīvniekam, t.i. šīs terapijas “blakus efektus".&Quot; Disease " specifically contains any unhealthy condition of an animal or part thereof and contains an unhealthy condition that could be caused or likely to be associated with medical or veterinary therapy applied to this animal, i.e. side effects of this therapy ".

[0052] "Atvasināts” nozīmē līdzīgu līdzekli, kuru var noteikt.&Quot; Derived " means a similar feature that can be identified.

[0053] "Kaitīga imūna reakcija” nozīmē imūnu reakciju, kas aizkavē efektīvu pacienta ārstēšanu vai izraisa slimību pacientā. Piemēram, ievadot pacientam peļu antivielu - kā terapiju vai diagnostikas nolūkā, notiek cilvēka pretpeļu antivielu veidošanās, kas aizkavē vai traucē turpmāku ārstēšanu. Antivielu veidošanās attiecībā pret tīrām peļu monoklonālām antivielām var pārsniegt 70% (skat. Khazaeli, Μ. B. etal. J. lmmwiother. 1994, 15, pp 42-52; Dillman R. O. etal. Cancer Biother. 1994, 9, pp 17- 28; un Reinsberg, J. Hybridoma. 1995, 14, pp 205-208). Papildu piemēri zināmiem līdzekļiem, kas cieš no kaitīgas imūnās reakcijas, ir tādi asins sarecēšanas faktori, tādi kā faktors VIII. Faktors VIII, kad ievadīts pacientiem, kuriem ir hemofīlija A, atjauno asins sarecēšanas spēju. Kaut gan faktors VIII ir cilvēka proteīns, tas tomēr izraisa imūno reakciju pacientos ar hemofīliju, jo viņu asinīs nav endogēnā faktora VIII un tātad tas izrādās svešais antigēns imūnajai sistēmai. Ap 29-33% no jauniem pacientiem producē antivielas, kas saista un neitralizē terapeitiski ievadīto.faktoru VIII (skat. LusherJ. M. Semin Thromb Hemost. 2002, 28(3), pp.273-276). Šīs neitralizējošās antivielas prasa lielāku faktora VIII daudzuma ievadīšanu, lai uzturētu normālos asins sarecēšanas parametrus, dārgu ārstēšanas režīmu, lai inducētu imūno pārnesamību (skat. BrietEetal. Adv. Exp. Med. Bio. 2001, 489, pp 89-97). Cits imunogēnais piemērs ir adenovīrusu vektori. Reirovīrusu terapija joprojām ir eksperimentāla un pielietojama ierobežoti. Viens no iemesliem irtas, ka terapeitiskā vīrusa lietošana izraisa imūno reakciju, kas var bloķēt jebkādu tā paša vai līdzīga vīrusa ievadīšanu (skat. Yiping Yang etal. J. ofVirology. 1995, 69, pp 2004-2015). Tas nodrošina, ka, retrovīrusu terapijām jāpamatojas uz proteīna mainīgo parādīšanos vai tiešu vīrusa secības iekļaušanu saimnieka genomā. Mērķtiecīgie pētījumi ļāva identificēt vairākus vīrusus neitralizējošus epitopus, kurus atpazīst saimnieka antivielas (skat. Hanne, Gahery-Segard et al. J. of Virology 1998. 72, pp 2388-2397), parādot, ka ar vīrusu modifikācijām nepietiek, lai pārvarētu šo šķērsli. Šis izgudrojums ļaus realizēt procesu, kurā adenovīrusu terapiju varēs pielietot atkārtoti. Vēl viens piemērs, kurā imunogēnais preparāts izraisa neitralizējošo antiveilu veidošanos, ir labi pazīstāmais kosmētiskais līdzeklis Botox. Botulīna toksīna proteīns ir attīrīts no Clostridium botulinum fermentācijas. Kā terapeitisku līdzekli to pielieto muskuļu traucējumu gadījumos, tādos kā kakla distonija, papildus kosmētiskam pielietojumam. Pēc atkārtotas pielietošanas pacientos veidojās neitralizējošās antivielas pret toksīnu, kā rezultātā samazinās efektivitāte (skat. Blrklein F. etal. Ann Neurol. 2002, 52, pp 68-73 un Rollntk, J. D. etal Neurol. Clīn. Neurophysiol. 2001, 2001(3), pp 2-4). “Kaitīga imūna reakcija” ietver arī slimības, kuras izraisa terapeitiski līdzekļi. Konkrēts piemērs tam ir imūnā reakcija uz terpapiju ar rekombinanto cilvēka eritroproteīnu (EPO). Eritroproteīnu izmanto, lai veicinātu sarkano šūnu augšanu un atjaunotu sarkano asins šūnu skaitu pacientos pēc ķīmijas terapijas vai dialīzes. . 9 9 LV 13669&Quot; Harmful immune response " means an immune response that inhibits effective patient treatment or causes a disease in a patient. For example, by administering a mouse antibody to a patient for therapeutic or diagnostic purposes, the development of human anti-murine antibodies is delayed or delayed by further treatment. Antibody formation against pure mouse monoclonal antibodies may exceed 70% (see Khazaeli, B. et al. J. lmmwiother. 1994, 15, pp. 42-52; Dillman RO et al. Cancer Biother. 1994, 9, pp. 17- 28; and Reinsberg, J. Hybridoma, 1995, 14, pp. 205-208). Additional examples of known agents that suffer from a harmful immune response are blood coagulation factors such as factor VIII. Factor VIII when administered to patients with haemophilia A restores blood coagulation. Although Factor VIII is a human protein, it does cause an immune response in patients with haemophilia, because they do not have endogenous factor VIII in their blood and thus appear to be a foreign antigen to the immune system. About 29-33% of young patients produce antibodies that bind and neutralize the therapeutically-administered factor VIII (see LusherJ M. Semin Thromb Hemost. 2002, 28 (3), pp.273-276). These neutralizing antibodies require a higher intake of factor VIII to maintain normal blood coagulation parameters, an expensive treatment regimen to induce immune transferability (see BrietEetal. Adv. Exp. Med. Bio. 2001, 489, pp. 89-97). Another immunogenic example is the adenoviral vectors. Reirovirus therapy is still experimental and limited. One reason for this is that the use of therapeutic virus causes an immune response that can block any of the same or similar virus (see Yiping Yang et al. J. ofVirology. 1995, 69, pp. 2004-2015). This ensures that retroviral therapies should be based on the appearance of protein variables or direct inclusion of the viral sequence in the host genome. Targeted studies allowed the identification of several virus-neutralizing epitopes recognized by host antibodies (see Hanne, Gahery-Segard et al. J. of Virology 1998 72, pp. 2388-2397), showing that virus modifications are not sufficient to overcome this obstacle . This invention will allow the process of re-administration of adenoviral therapy to be realized. Another example of an immunogenic product that causes neutralizing antiviral is the well-known Botox. Botulinum toxin protein is purified from Clostridium botulinum fermentation. It is used as a therapeutic agent in muscular disorders such as cervical dystonia, in addition to cosmetic use. Following re-use, patients developed neutralizing antibodies to the toxin, resulting in reduced efficacy (see Blarclein et al. Ann Neurol. 2002, 52, pp. 68-73 and Rollntk, JD et al. Neurol. Clin. Neurophysiol. 2001, 2001 (3) , pp. 2-4). "Harmful immune response" also includes diseases caused by therapeutic agents. A specific example of this is the immune response to the therapy with recombinant human erythropoietin (EPO). Erythroprotein is used to promote red cell growth and to restore red blood cell count in patients after chemotherapy or dialysis. . 9 9 EN 13669

Procentuāli maz pacientos veidojas antivielas pret EPO un pēc tam šie pacienti nereaģē ne uz terapeitiski ievadāmo EPO, ne uz viņu pašu endogēno EPO (skat. Casadevall, N, etal, NEJM. 2002, 346, pp 469-475). Šajos pacientos veidojas traucējums, tīro sarkano šūnu aplāzija, kuras gadījumā sarkano asins šunu producēšana strauji samazinās (skat. Gershon S. K. et. ai NEJM. 2002, 346, pp 1584-1586). Šī EPO terapijas komplikācija var būt letāla, ja to neārstē. Cits konkrēts piemērs ir peļu antiviela OKT3 (pazīstama arī kā Orthoclone) -monoklonāla antiviela, kas vērsta uz aktivēto T-šūnu CD-3 domēnu. Klīniskajos izmēģinājumos 20-40% pacientu gadījumā OKT3 ievadīšanas rezultātā veidojas antivielas pret terapiju. Bez terapijas neitralizēšanas, šīs antivielas stimulē arī spēcīgu saimnieka imūno reakciju. Imūnā reakcija ir pietiekami spēcīga, lai pacientiem ar lielām cilvēka pretpeļu antivielu koncentrācijām liegtu zāju ievadīšanu (skat. etiķeti uz 'Orthoclone” iepakojuma). Pēdējais piemērs ir cilvēka antivielas terapeitisks līdzeklis. Humira® ir monoklonāla antiviela, kas vērsta pret TNF un ko izmanto reimatoīdā artrīta ārstēšanai. Lietojot tikai šo antivielu, ~12% pacientu producē neitralizējošās antivielas. Bez tam, izsakot procentos, mazā pacientu skaitā, kam ievada zāles, veidojas sistēmiskajam lupus erthematosus līdzīgais stāvoklis, kas ir terapeitiska līdzekļa izraisītā imūnā reakcija ar IgG starpniecību (skat. etiķeti uz “Humira"iepakojuma).A small percentage of patients develop antibodies to EPO and then these patients do not respond to either the therapeutically-administered EPO or their own endogenous EPO (see Casadevall, N, et al., NEJM. 2002, 346, pp. 469-475). These patients develop a disorder of pure red cell aplasia, in which red blood cell production is rapidly decreasing (see Gershon S.K. et al. NEJM 2002, 346, pp. 1584-1586). This complication of EPO therapy can be fatal if left untreated. Another specific example is the mouse antibody OKT3 (also known as Orthoclone) monoclonal antibody directed to the activated T-cell CD-3 domain. In clinical trials in 20-40% of patients, administration of OKT3 results in anti-therapy antibodies. In addition to neutralizing therapy, these antibodies also stimulate a strong host immune response. The immune response is strong enough to deny entry to patients with high levels of anti-human antibody antibodies (see label on 'Orthoclone' packaging). The last example is the therapeutic agent for human antibodies. Humira® is a monoclonal antibody directed against TNF and used to treat rheumatoid arthritis. Using only this antibody, ~ 12% of patients produce neutralizing antibodies. Additionally, expressed as a percentage of the small number of patients being given the medicine, a systemic lupus erthematosus-like condition develops as a therapeutic-mediated immune response via IgG (see the label on the Humira package).

[0054] Vēl viens “kaitīgas imūnās reakcijas” piemērs ir saimnieka reakcija uz mazu molekulu zālēm. Šīs nozares speciālistiem zināms, ka noteiktas ķīmiskās struktūras savienojas ar saimnieka proteīniem, stimulējot imūno atpazīšanu (skat. Ju. C. etal. 2002. CurrentDrug Metabolism 3, pp 361 -111 un Kimber /. et ai. 2002, ToxicoIogic Patho!ogy 30, pp 54- 58.) Ievērojama šo saimnieka reakciju daļa notiek ar IgG starpniecību. Konkrētās “kaitīgās imūnās reakcijas” ar IgG starpniecību ir hemolītiskā anēmija, Stīvena-•Džonsona sindroms un zāļu inducētais Lupus.Another example of a "harmful immune response" is a host response to a small molecule drug. It is known to those skilled in the art that certain chemical structures bind to host proteins by stimulating immune recognition (see Ju.C. etal. 2002 CurrentDrug Metabolism 3, pp. 361-111 and Kimber / et al. 2002, ToxicoIogic Patho! pp. 54-58.) Significant part of these host reactions occurs via IgG. Specific 'harmful immune responses' via IgG are haemolytic anemia, Steven-Johnson syndrome and drug-induced Lupus.

[0055] "Halogēns" nozīmē fluora, hlora, broma vai joda atomu.&Quot; Halogen " means fluorine, chlorine, bromine or iodine.

[0056] "Haloaikilgrupa" nozīmē iepriekš definēto alkilgrupu, kas aizvietota ar vienu vai vairākiem, piemēram, no viena līdz trīspadsmit, labāk no viena līdz septiņiem “halogēna” atomiem, kā šie nosacījumi definēti šajā pieteikumā. Haloaikilgrupa satur monohaloalkilgrupu, dihaloalkilgrupu, trihaloalkilgrupu, perhaloalkilgrupu un tamlīdzīgi, piemēram, hlormetilgrupu, dihlormetilgrupu, difluormetilgrupu, trifluormetilgrupu, 2,2,2-trifiuoretilgrupu, perfluoretilgrupu, 2,2,2-trifluor-1,1 -dīhloretilgrupu un tamlīdzīgi.&Quot; Haloaikil " means an alkyl group, as defined above, substituted with one or more, e.g. from one to thirteen, preferably from one to seven halogen atoms, as defined in this application. The haloalkyl group contains monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like, such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.

[0057] "Haloalkīlēngrupa" nozīmē alkilēna atlikumu kā definēts iepriekš, kur viens no četriem, labāk viens vai divi ūdeņraža atomi alkilēna ķēdē aizvietots(i) ar fluora atomu(iem).&Quot; Haloalkylgroup " means an alkylene residue as defined above wherein one of the four, preferably one or two, hydrogen atoms in the alkylene chain is (are) substituted by fluorine (s).

[0058] "Haloalkoksigrupa" nozīmē -OR atlikumu, kur R ir haloaikilgrupa kā definēts iepriekš, piemēram, trifluormetoksigrupa, 2,2,2-trifluoretoksigrupa, difluormetoksigrupa un tamlīdzīgi.&Quot; Haloalkoxy " means -OR, wherein R is haloalkyl as defined above, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy and the like.

[0059] "Heteroarilgrupa" kā grupa vai grupas daļa nozīmē aromātisku monociklisku vai biciklisku funkcionālu grupu ar 5 līdz 10 gredzena atomiem, 10 kurā vienu vai vairākus, labāk vienu, divus vai trīs gredzena atomus izvēlas no slāpekļa, skābekļa vai sēra un pārējie gredzena atomi ir ogleklis. Heieroarila gredzena piemēri ir, ar minēto neierobežojoties, pirolila, furanila, tīenila, oksazolila, izoksazolila, tiazolila, imidazolila, triazolila, tetrazolila, piridinila, pirimidinila, pirazinila, piridazinila, indolila, benzofuranila, benzotiofenila, benzimidazolila, hinolinila, izohinolinila, hinazolinila, hīnoksalinila, pirazolila gredzens un tamlīdzīgi.&Quot; Heteroaryl " as a group or part of a group means an aromatic monocyclic or bicyclic functional group having 5 to 10 ring atoms, wherein one or more, preferably one, two or three ring atoms are selected from nitrogen, oxygen or sulfur, and the other ring atoms are carbon. Examples of the Heeroaryl ring include, without limitation, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalineil , pyrazolyl ring and the like.

[0060] "Heteroariloksigrupa" nozīmē -O-R atlikumu, kur R ir heteroarilgrupa kā definēts iepriekš, piemēram, furaniloksigrupa, piridiniloksigrupa, indoliloksigrupa un tamlīdzīgi.&Quot; Heteroaryloxy " means -O-R, wherein R is heteroaryl as defined above, for example furanyloxy, pyridinyloxy, indolyloxy, and the like.

[0061] "Heteroariloksikarbonilgrupa" nozīmē -C(0)0-R atlikumu, kur R ir heteroarilgrupa kā definēts iepriekš, piemēram, piridiniloksikarbonilgrupa, pirimidiniloksikarbonilgrupa un tamlīdzīgi.&Quot; Heteroaryloxycarbonyl " means a residue of -C (O) 0-R, wherein R is heteroaryl as defined above, for example, pyridinyloxycarbonyl, pyrimidinyloxycarbonyl and the like.

[0062] "Heteroaralkilgrupa" nozīmē -(alkilēn)-R atlikumu, kur R ir heteroarilgrupa kā definēts iepriekš, piemēram, piridinilmetilgrupa, 1- vai 2-furaniletilgrupa, imidazolilmetilgrupa un tamlīdzīgi.&Quot; Heteroaralkyl " means a - (alkylene) -R residue wherein R is heteroaryl as defined above, for example, pyridinylmethyl, 1- or 2-furanylethyl, imidazolylmethyl and the like.

[0063] "Heieroaralkiioksigrupa" ir-O-R atlikums, kur R ir heteroaralkilgrupa kā definēts iepriekš, piemēram, piridinilmetiloksigrupa, furaniletiloksigrupa un tamlīdzīgi.&Quot; Heroeroid Chemistry " is a -O-R residue wherein R is a heteroaralkyl group as defined above, for example, pyridinylmethyloxy, furanylethyloxy, and the like.

[0064] "Heteroaralkiloksikarbonilgrupa " nozīmē -C(0)0-R atlikumu, kur R ir heteroaralkilgrupa kā definēts iepriekš, piemēram, piridinilmetiloksikarbonilgrupa, pirimidinilmetiloksikarbonilgrupa un tamlīdzīgi.&Quot; Heteroaralkyloxycarbonyl " means a residue of -C (O) 0-R, wherein R is heteroaralkyl as defined above, for example, pyridinylmethyloxycarbonyl, pyrimidinylmethyloxycarbonyl, and the like.

[0065] "Heterocikloalkilgrupa" nozīmē piesātinātu vai daļēji piesātinātu monociklisko vai biciklisko atlikumu ar 4, 5 vai 6 oglekļa gredzena atomiem, kur vienu vai vairākus, labāk vienu, divus vai trīs gredzena oglekļa atomus aizvieto ar heteroatomu, kas izvēlēts no -N=, -N-, -O-, -S-, -SO- vai -S(0)2-, un turklāt kur vienu vai divus gredzena oglekļa atomus aizvieto ar keto (- CO-) grupu. Heterocikloalkila gredzenu neobligāti sakausē, veidojot cikloalkila, arila vai heieroarila gredzenu kā definēts šajā pieteikumā. Raksturīgākie piemēri ir, ar minēto neierobežojoties, imidazolidinilgrupa, morfoiinilgrupa, tiomorfolinilgrupa, tiomorfolin-1-oksīds, tiomorfolin-1,1- dioksīds, tetrahidrofuranilgrupa, tetrahīdropiranilgrupa, tetrahidrotiopiranilgrupa, 1-okso-tetrahidrotiopiranilgrupa, 1,1 -dioksotetratio-piranilgrupa, indolinilgrupa, piperazinilgrupa, piperidilgrupa, pirolidinilgrupa, pirolinilgrupa, hinuklidinilgrupa, 3,4-dihidroizohinolinilgrupa, dihidroindolilgrupa un tamlīdzīgi.&Quot; Heterocycloalkyl " means a saturated or partially saturated monocyclic or bicyclic residue with 4, 5 or 6 carbon ring atoms, where one or more, preferably one, two or three ring carbon atoms are replaced by a heteroatom selected from -N =, -N-, -O -, -S-, -SO-, or -S (O) 2 -, and further wherein one or two ring carbon atoms are replaced by a keto (- CO -) group. The heterocycloalkyl ring is optionally fused to form a cycloalkyl, aryl or hexeroaryl ring as defined in this application. Typical examples include, without limitation, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetratio-pyranyl, indolinyl, indolinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrolinyl, quinuclidinyl, 3,4-dihydroisoquinolinyl, dihydroindolyl, and the like.

[0066] Ja heterocikloalkilgrupa satur vismaz vienu slāpekļa atomu, šeit šī grupa nozīmē heterocikloaminogrupu un ir iepriekš definētās heterocikloalkilgrupas paveids.If the heterocycloalkyl contains at least one nitrogen atom, this group means a heterocycloamino group and is a heterocycloalkyl group as defined above.

[0067] "Heterociklilalkilēngrupa" ir divvērtīga heterociklilgrupa kā definēts šajā pieteikumā, un piemērs, kad “R3 un R4 kopā ar oglekļa atomu, pie kura pievienoti R3 un R4, veido heterociklīlalkilēnu" satur, bet ar minēto neierobežojoties, sekojošo: 11&Quot; Heterocyclylalkylene " is a bivalent heterocyclyl as defined in this application, and an example where "R3 and R4 together with the carbon to which R3 and R4 are attached form a heterocyclylalkylene" " contains, but without limitation, the following: 11

LV 13669 kur R ir aizvietotājs, kas definēts izgudrojuma kopsavilkuma.LV 13669 wherein R is a substituent as defined in the Summary of Invention.

[0068] "Heterocikloalkilalkilgrupa" nozīmē R atlikumu, kur R ir heterocikloalkilgrupa kā definēts iepriekš, piemēram, pirolidinilmetilgrupa, tetrahidrofuraniletīlgrupa, piridinilmetilpiperidinilmetilgrupa un tamlīdzīgi.&Quot; Heterocycloalkylalkyl " means R, wherein R is heterocycloalkyl as defined above, for example, pyrrolidinylmethyl, tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

[0069] "Heterocikloalkiloksikarbonilgrupa" nozīmē -C(0)0R atlikumu, kur R ir heterocikloalkilgrupa kā definēts iepriekš, piemēram, piridiniloksikarbonilgrupa, pirimidiniloksikarbonilgrupa un tamlīdzīgi.&Quot; Heterocycloalkyloxycarbonyl " means a residue of -C (O) 0R, wherein R is heterocycloalkyl as defined above, for example, pyridinyloxycarbonyl, pyrimidinyloxycarbonyl and the like.

[0070] "Hidroksiigrupa" nozīmē -OH atlikumu. Ja nav noteikts citādi, savienojumi, kas minēti šajā izgudrojumā un satur hidroksila radikāļus, satur arī to aizsargātos atvasinājumus. Piemērotās aizsargājošās grupas hidroksilgrupām ir benzilgrupas un tamlīdzīgi.&Quot; Hydroxy " means -OH residue. Unless otherwise stated, the compounds mentioned in the present invention containing hydroxyl radicals also contain their protected derivatives. Suitable protecting groups for hydroxyl groups are benzyl and the like.

[0071] "Hidroksialkilgrupa" nozīmē lineāru vienvērtīgu ogļūdeņraža atlikumu ar vienu līdz sešiem oglekļa atomiem vai sazarotu vienvērtīgu ogļūdeņraža atlikumu ar trim līdz sešiem oglekļa atomiem, kas aizvietoti ar vienu vai divām hidroksilgrupām, ar nosacījumu, ka, ja klāt ir divas hidroksilgrupas, tās nav savienotas ar vienu un to pašu oglekļa atomu. Raksturīgākie piemēri satur, bet ar minēto neierobežojoties, hidroksimetilgrupu, 2-hidroksietilgrupu, 2-hidroksipropilgrupu, 3-hidroksipropilgrupu, 1-(hidroksimetil)-2-metilpropilgrupu, 2-hidroksibutiJgrupu, 3-hidroksibutilgrupu, 4-hidroksibutilgrupu, 2,3-dihidroksipropilgrupu, 1- (hidroksimeiil)-2-hidroksietilgrupu, 2,3-dihidro'ksibutilgrupu, 3,4-dihidroksibutilgrupu un 2-(hidroksimetiI)-3-hidroksipropīlgrupu, labāk 2-hidroksietilgrupu, 2,3-dihidroksipropilgrupu un 1-(hidroksimetil)-2-hidroksietilgrupu.&Quot; Hydroxyalkyl " means a linear equal hydrocarbon residue with one to six carbon atoms or a branched, mono-hydrocarbon residue with three to six carbon atoms substituted with one or two hydroxyl groups, provided that when two hydroxyl groups are present, they are not linked to the same carbon atom; carbon atoms. Typical examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl , 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydro-oxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- (hydroxymethyl) ) -2-hydroxyethyl.

[0072] "Izornēri" nozīmē savienojumus ar formulu (l), kuriem ir identiska molekulāra formula, bet kuri atšķiras arto atomu savienošanās raksturu vai secību vai to atomu telpisko izvietojumu. Izomērus, kas atšķiras arto atomu telpisko izvietojumu, dēvē par “stereoizornēriem”. Stereoizomērus, kas ir cits cita spoguļattēls, dēvē par “diastereoizomēriem” un stereoizomērus, kas nav virsū uzliekamie spoguļattēli, dēvē par “enantiomēriem” vai dažkārt par “optiskajiem izomēriem”. Oglekļa atomu, kas savienots ar četriem neidentis'kiem aizvietotājiem, dēvē par “hirālo centru”. Savienojumus ar vienu hīrālo centru, kuram ir divas enantiomēriskās formas ar pretēju 'hiralitāti, dēvē par “racēmisku maisījumu". Savienojumam, kuram ir vairāk kā viens hirālais centrs, ir 2n"1 enantiomēru pāri, kur n ir hirālo centru skaits. Savienojumi ar vairāk kā vienu hirālo centru var eksistēt kā individuāls diastereomērs vai arī kā diastereomēru maisījums, ko dēvē par “diastereomēru maisījumu”. Ja savienojumam ir viens hirālais centrs, stereoizomēru varētu raksturot ar hirālā centra absolūto konfigurāciju. Absolūtā konfigurācija nozīmē veidu, kādā telpā sakārtoti, aizvietotāji, kas savienoti ar hirālo centru. Enantiomēri raksturojami ar to hirālo centru absolūto konfigurāciju un aprakstāmi ar Kāna, Ingolda un Preloga R- un S-secības noteikumiem. Stereoķīmijas nomenklatūras 12 vispārpieņemtie noteikumi, stereoķīmijas noteikšanas un stereoizomēru atdalīšanas paņēmiens ir labi pazīstami nozarē (piemēram, skat. "Advanced Organic Chemistry", 4th ea'ition, March, Jerry, John Wiley & Sons, New York, 1992). Skaidrs, ka nosaukumi un ilustrācijas, kas šajā pieteikumā izmantotas savienojumu ar formulu (I) aprakstīšanai, satur visus iespējamos stereoizomērus.&Quot; Exorcists " means compounds of formula (I) having the same molecular formula, but which differ in the nature or sequence of attachment of the atoms or in the spatial distribution of their atoms. Isomers that differ in the spatial positioning of the atoms are called "stereoisors." Stereoisomers, which are a mirror image of one another, are called 'diastereoisomers' and stereoisomers that are not superimposed mirror images are called 'enantiomers' or sometimes 'optical isomers'. A carbon atom linked to four non-identical substituents is called a "chiral center". Compounds with one chiral center having two enantiomeric forms with opposite chirality are referred to as a "racemic mixture". The compound having more than one chiral center has 2n " 1 pair of enantiomers where n is the number of chiral centers. Compounds with more than one chiral center may exist as an individual diastereomer or as a mixture of diastereomers, called a "diastereomeric mixture". If the connection has one chiral center, the stereoisomer could be characterized by the absolute configuration of the chiral center. Absolute configuration means the way the space is arranged, the substitutes connected to the chiral center. The enantiomers are characterized by the absolute configuration of their chiral centers and described by the rules of the R- and S-sequences of Cane, Ingold and Preloga. The generally accepted rules of the stereochemistry nomenclature 12, the method for the detection of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see " Advanced Organic Chemistry ", 4th ea'ition, March, Jerry, John Wiley & Sons, New York, 1992). It is clear that the names and illustrations used in this application to describe compounds of formula (I) contain all possible stereoisomers.

[0073] "Neobligāts” vai “neobligāti”, vai “var būt” nozīmē, ka pēc šiem vārdiem minētais notikums vai apstāklis var notikt vai var nenotikt, un ka aprakstā ietverti piemēri, kad notikums vai apstāklis notiek, un piemēri, kad notikums vai apstāklis nenotiek. Piemēram, vārdi “kur aromātisko gredzenu Ra neobligāti aizvieto ar vienu vai diviem aizvietotājiem, kas neatkarīgi izvēlēts no alkilgrupas” nozīmē, ka aromātisko gredzenu var aizvietot vai var neaizvietot ar alkilgrupu, lai atbilstu izgudrojuma ietvariem.&Quot; Optional " or " optional " or " may be " means that, after these words, the event or circumstance may or may not occur, and that the description includes examples of when an event or circumstance occurs and examples of an event or the circumstance does not happen. For example, the words "wherein the aromatic ring Ra is optionally substituted with one or two substituents independently selected from alkyl" means that the aromatic ring may be substituted or may not be substituted by an alkyl group to match the scope of the invention.

[0074] Šis izgudrojums satur arī savienojuma ar formulu (I) N-oksīda atvasinājumus. N-oksīda atvasinājums nozīmē savienojumu ar formulu (I), kurā slāpekļa atoms ir oksidēts (t.i., N-* 0), piemēram, piridina N-oksīds, un kuram ir vēlamā farmakoloģiskā aktivitāte.The present invention also includes N-oxide derivatives of a compound of formula (I). An N-oxide derivative means a compound of formula (I) wherein the nitrogen atom is oxidized (i.e., N- * 0), for example, pyridine N-oxide, and which has the desired pharmacological activity.

[0075] Slimības “patoloģija” nozīmē.slimības būtisko dabu, iemeslus un · attīstību, kā arī strukturālās up funkcionālās izmaiņas, kuras ir slimības procesu rezultāts.Disease “pathology” means the essential nature of the disease, the causes and the development, as well as the structural functional changes that are the result of the disease processes.

[0076] "Farmaceitiski pieņemams” nozīmē to, ka, ja kaut kas ir lietderīgs farmaceitiskas kompozīcijas pagatavošanai, parasti tas ir arī drošs, netoksisks un nav nevēlams ne bioloģiski, ne citādi un satur to, kas pieņemams lietošanai veterinārijā, kā arī cilvēku farmaceitiskai lietošanai.&Quot; Pharmaceutically acceptable " means that if something is useful for the preparation of a pharmaceutical composition, it is usually also safe, non-toxic and not undesirable either biologically or otherwise and contains what is acceptable for veterinary use as well as human pharmaceuticals. for use.

[0077] "Farmaceitiski pieņemams sāls” nozīmē savienojuma ar formulu (I) sājus, kuri ir farmaceitiski pieņemami kā definēts iepriekš un kuriem ir vēlamā farmakoloģiskā aktivitāte. Šie sāji satur skābes pievienošanas sāļus, kas veidojas ar neorganiskajām skābēm, tādām kā sālsskābe, bromūdeņskābe, sērskābe, slāpekļskābe, fosforskābe un tamlīdzīgi; vai ar organiskajām -skābēm, tādām kā etiķ-skābe, propionskābe, heksānskābe, heptānskābe, ciklopentānpropionskābe, glikolskābe, pervīnogskābe, oksipropionskābe, malonskābe, sukcīnskābe, ābolskābe, maleīnskābe, fumārskābe, vīnskābe, citronskābe, benzoskābe, o-(4-hidroksibenzoil)benzoskābe, kanēļskābe, mandeiskābe, metilsulfonskābe, etānsulfonskābe, 1,2-etāndisulfonskābe, 2-hidroksietēnsulfonskābe, benzolsulfonskābe, p-hlorobenzolsulfonskābe, 2-naftalīnsulfonskābe, kamparsulfonskābe, 4-metilbiciklo[2.2.2]okt-2-en-1-karboksilskābe, glikoheptonskābe, 4,4'-metiiēnbis(3-hidroksi-2-en-1-karboksilskābe), 3-fenilpropionskābe, trimetiletiķskābe, terciārā butiletiķskābe, laurilsērskābe, glukonskābe, glutāmskābe, hidroksinaftoskābe, salicilskābe, stearīnskābe, mukonskābe un tamlīdzīgi.&Quot; Pharmaceutically acceptable salt " means a salt of a compound of formula (I) which is pharmaceutically acceptable as defined above and which has the desired pharmacological activity. These salts contain acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic-acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentane propionic acid, glycolic acid, pervinic acid, oxypropionic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid , cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethylene sulphonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camparulfonic acid, 4-methylbicyclo [2.2.2] oct-2-en-1-carboxylic acid, glycoheptonic acid , 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, laurylic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

[0078] Farmaceitiski pieņemami sāļi satur arī bāzes pievienošanas sāļus, kas varētu veidoties, ja esošie skābes protoni spēj reaģēt ar neorganiskajām vai organiskajām bāzēm. Pieņemamas neorganiskās bāzes satur nātrija hidroksīdu, nātrija karbonātu, kālija hidroksīdu, alumīnija hidroksīdu un kalcija 13 13 LV 13669 hidroksīdu. Pieņemamas organiskās bāzes satur etanolamīnu, dietanolamīnu, trietanolamīnu, trimetamīnu, N-metilglukamīnu un tamlīdzīgi.Pharmaceutically acceptable salts also contain base addition salts which may be formed when the existing acid protons are capable of reacting with inorganic or organic bases. Acceptable inorganic bases contain sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium 13 13 LV 13669 hydroxide. Acceptable organic bases contain ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine and the like.

[0079] Šis izgudrojums satur arī savienojuma ar formulu (I) prozāles. Prozāles nozīmē savienojumu, kas pārvēršams in vivo metaboliskajā veidā (piemēram, ar hidrolīzi), veidojot savienojumu ar formulu (I). Piemēram, savienojuma ar formulu (i) esteris, kas satur hidroksīlgrupu, var tikt pārvērsts sākotnējā formulā ar hidrolīzi in vivo. Vai arī savienojuma ar formulu (I) esteris, kas satur karboksilgrupu, var tikt pārvērsts sākotnējā savienojumā ar hidrolīzi in vivo. Piemērotie savienojuma ar formulu (I) esteri, kas satur hidroksīlgrupu, ir, piemēram, acetāti, citrāti, laktāti, tartrāti, malonātī, oksalāti, salicīlāti, propionāti, sukcināti, fumarāti, maleāti, methilēn-bis-pb-hidroksinaftoāti, gentizati, izotionāti, di-p-toluoltartrāti, metilsulfonāti, etānsulfonāti, benzolsulfonāti, p-toluolsulfonāti, cikloheksilsulfamāti un hināti. Piemērotus savienojumu ar formulu (I) esterus, kas satur karboksilgrupu, aprakstīja Leinvveber, FJ. DrugMetab. Res., 1987, 18, page 379. īpaši lietderīgos savienojumu ar formulu (I) esterus, kas satur hidroksīlgrupu, var veidot no skābes funkcionālajām grupām, ko izvēlas no tām, kuras aprakstīja Bundgaard et ai, J. Med. Chem., 1989, 32, pp 2503-2507, un kas satur aizvietotus (aminometil) benzoāius, piemēram, dialkilaminometilbenzoātus, kuros divas alkilgrupas var tikt savienotas un/vai nodalītas ar skābekļa atomu vai neobligāti aizvietotu slāpekļa atomu, piemēram, alkilētu slāpekļa atomu, un konkrētāk (morfolīnmetil)benzoāti, piemēram, 3- vai 4-(morfolīnmetil)benzoāts un (4-alkilpiperazin-1-il)benzoāti, piemēram, 3- vai 4-(4-alki!piperazin-1-il)benzoāti.[0079] The present invention also includes the prodrugs of the compound of formula (I). Prose means a compound that is converted in vivo into a metabolic form (e.g., by hydrolysis) to form a compound of formula (I). For example, an ester of a compound of formula (i) that contains a hydroxyl group may be converted to the original formula by hydrolysis in vivo. Or, an ester of a compound of formula (I) containing a carboxyl group may be converted to the initial hydrolysis in vivo. Suitable esters of a compound of formula (I) containing a hydroxyl group include, for example, acetates, citrates, lactates, tartrates, malonate, oxalates, salicylates, propionates, succinates, fumarates, maleate, methylene bis-pb-hydroxynaphthates, gentisates, isothionates , di-p-toluene tartrates, methylsulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and hexanes. Suitable esters of compounds of formula (I) containing a carboxyl group are described by Leinvveber, FJ. DrugMetab. Res., 1987, 18, page 379. Especially useful esters of compounds of formula (I) containing a hydroxyl group may be formed from acid functional groups selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, pp. 2503-2507, containing substituted (aminomethyl) benzoates, such as dialkylaminomethylbenzoates, in which two alkyl groups can be bonded and / or separated by an oxygen atom or an optionally substituted nitrogen atom such as an alkylated nitrogen atom; and more specifically (morpholymethyl) benzoates such as 3- or 4- (morpholinomethyl) benzoate and (4-alkylpiperazin-1-yl) benzoates such as 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

[0080] "Aizsargātie atvasinājumi” nozīmē savienojumu ar formulu (I) atvasinājumus, kuros reaktīva zona vai zonas nobloķētas ar aizsargājošām grupām. Savienojumu ar formulu (I) aizsargātie atvasinājumi izmantojami, pagatavojot savienojumus arformulu (I) vai arī paši varētu būt aktīvie katepsīna S inhibitori. Plašs piemērotu aizsargājošo grupu uzskaitījums minēts T. W. Greene, Protective Groupsin Organic Synthesis, 3rd edition,&Quot; Protected Derivatives " means derivatives of compounds of formula (I) in which the reactive zone or zones are blocked by protecting groups. The protected derivatives of the compounds of formula (I) may be used in the preparation of compounds of formula (I) or may be active cathepsin S inhibitors themselves. An extensive list of suitable protective groups is listed in T. W. Greene, Protective Groupsin Organic Synthesis, 3rd edition,

John Wiley & Sons, Inc. 1999.John Wiley & Sons, Inc. 1999

[0081] "Terapeitiski efektīvs daudzums” nozīmē daudzumu, kurš, ievadot dzīvniekam slimības ārstēšanas nolūkā, ir pietiekams, lai nodrošinātu šīs slimības ārstēšanu.&Quot; Therapeutically effective amount " means the amount that is sufficient for treating the disease for the animal to treat the disease.

[0082] "Ārstēšana” vai “ārstēt” nozīmē jebkādu šajā izgudrojumā aprakstītā savienojuma ievadīšanu un satur sekojošo: (1) slimības izcelšanās novēršanu dzīvniekā, kurš varētu būt disponēts uz slimību, bet pagaidām vēl neizjūt vai neizrāda slimības patoloģiju vai simptomatoloģiju, (2) slimību inhibēšanu dzīvniekā , kas izjūt vai izrāda slimības patoloģiju vai simptomatoloģiju (t.i., novērsi turpmāko slimības patoloģijas un/vai' simptomatoloģijas attīstību), vai 14 (3) slimības mazināšanu dzīvnieka, kas izjūt vai izrāda slimības patoloģiju vai sīmptomatoloģiju (t.i., mainīt slimības patoloģiju un/vai simptomatoioģiju). "Ārstēšana” vai “ārstēt” attiecībā pret kombinēto terapiju, t.i., ja kopā ar bioloģiskajiem preparātiem ievada šajā izgudrojumā aprakstīto savienojumu, satur: (1) imūnās reakcijas izcelšanās novēršanu dzīvniekā, kurš varētu būt disponēts uz imūno reakciju, bet pagaidām vēl neizjūt vai neizrāda imūnās reakcijas patoloģiju vai simptomatoioģiju, (2) imūno reakciju inhibēšanu dzīvniekā, kas izjūt vai izrāda imūnās reakcijas patoloģiju vai simptomatoioģiju (t.i., novērst turpmāko patoloģijas un/vai simptomatoloģijas attīstību), vai (3) imūno reakciju mazināšanu dzīvniekā, kas izjūt vai izrāda imūnās reakcijas patoloģiju vai simptomatoioģiju (t.i., mazināt imūnās reakcijas līmeni vai smagumu, vai pakāpi, vai ilgumu, atklātas izpausmes vai mainīt patoloģiju un/vai simptomatoioģiju, piemēram, samazināt a.ntigēnu peptīdu saistīšanu un radīšanu arMHC II klases molekulām, samazinātu T-šūnu un B-šūnu aktivāciju, samazinātās humorālās reakcijas un reakcijas, kuru starpnieces ir šūnas, un, atbilstoši atsevišķām imūnajām reakcijām samazinātu iekaisumu, pieplūšanu ar asinīm, sāpes, nekrozi, samazinātu bioloģiskā preparāta efektivitāti un tamlīdzīgi).&Quot; Treatment " or " treat " means any administration of a compound described in the present invention and comprising the following: (1) preventing the onset of disease in an animal that may be at the disposal of the disease but not yet experiencing or showing disease pathology or symptomology; ) the inhibition of disease in an animal suffering from or showing disease pathology or symptomology (ie preventing further development of disease pathology and / or 'symptomology'), or 14 (3) reduction of disease in an animal suffering from or showing disease pathology or symptomatic abnormalities (ie altering the disease) pathology and / or symptomatology). " Treatment " or " treat " with respect to combination therapy, i.e., when administered with the biological agents in combination with the invention described herein, comprises: (1) preventing an immune response in an animal that may have an immune response but not yet feeling or (2) inhibition of immune responses in an animal that is experiencing or exhibiting a pathological or symptomatic symptom of an immune response (ie preventing further development of pathology and / or symptomatology); or (3) reduction of immune response in an animal experiencing or exhibiting immunity. immune response pathology or symptomatology (ie to reduce the level or severity of the immune response, or the degree, or duration, manifestations, or alter the pathology and / or symptomology, for example, to reduce the binding and generation of antigenic antigens to MHC class II molecules, to reduce T-cell \ t and B-cell activation, reduced humoral reactions and reactions mediated by cells, and to reduce inflammation, blood flow, pain, necrosis, reduce the effectiveness of the biological product and the like, according to individual immune responses.

[0083] Vārdi “kur aromātisko vai aliciklisko gredzenu RD neobligāti aizvieto ar vienu, divām vai trim Ra, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas vai halogēna; vai neobligāti aizvieto ar vienu vai divām Rb, kas neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēta no hidroksialkilgrupas, alkoksialkilgrupas, aminoalkilgrupas, arilgrupas, heteroarilgrupas, araikilgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgrupas,..." R5 definējumā savienojumam ar formulu (I) nozīmē, ka visus tieši vai netieši pievienotos aromātiskos un alicikliskos gredzenus R5 (piemēram, R5 ir cikloalkiialkifgrupa, -alkilēn-X-R9, kurX ir kā definēts izgudrojuma kopsavilkumā, un R9 ir arilgrupa, aralkilgrupa utt.)” neobligāti aizvieto ar Ra, vai Rb un Rc, vai tikai ar R°.The words "wherein the aromatic or alicyclic ring RD is optionally substituted with one, two, or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaralkyl , cycloalkyl, cycloalkylalkyl, ... " R5 in the definition of a compound of formula (I) means that all directly or indirectly attached aromatic and alicyclic rings R5 (e.g., R5 is cycloalkylcyclo, -alkylene-X-R9 wherein X is as defined in the Summary of the Invention, and R9 is aryl, aralkyl, and the like. ) 'Is optionally substituted with Ra, or Rb and Rc, or only with R °.

Izgudrojuma realizācijas varianti, kuriem dodama priekšroka [0084] I. Priekšroka dodama noteiktiem savienojumiem ar formulu (I) visplašākajā izgudrojuma kopsavilkumā noteiktajā aspektā. Piemēram:. (A) Savienojumu grupa, kurai dodama priekšroka, irtā, kur: R1 ir ūdeņradis vai metilgrupa, labāk ūdeņradis; R2 ir ciklopropilgrupa, 1-feniletil [-0Η(06Η5)0Η3], vai 1 H-pīrazoI-5-il; labāk ciklopropilgrupa. 15 15 LV 13669 [0085] (1) Iepriekš minētajā (A) grupā, kurai dodama priekšroka, un grupā, kurai priekšroka dodama pirmām kārtām un kura pieder pie (A) grupas, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, irtā, kur R3 ir ūdeņradis un R4 ir alkilgrupa, labāk metilgrupa, etilgrupa, propilgrupa vai butiigrupa, vēl labāk, ja R4 ir etilgrupa vai propilgrupa.Preferred Embodiments of the Invention Preferred I. Preferred compounds of formula (I) are preferred in the broadest aspect of the invention. For instance:. (A) A preferred group of compounds is wherein: R 1 is hydrogen or methyl, preferably hydrogen; R2 is cyclopropyl, 1-phenylethyl [-0Η (06Η5) 0Η3], or 1H-pyrazo-5-yl; preferably cyclopropyl. 15 15 EN 13669 [0085] (1) In the aforementioned (A) group, which is preferred, and in the preferred group and belonging to group (A), the group of compounds that is preferred is where: R 3 is hydrogen and R 4 is alkyl, preferably methyl, ethyl, propyl or butyl, more preferably when R 4 is ethyl or propyl.

[0086] (2) Iepriekš minētajā (A) grupā, kurai dodama priekšroka, un grupā, kurai priekšroka dodama pirmām kārtām un kura pieder pie (A) grupas, savienojumu grupa, kurai priekšroka dodama pirmām kārtā, irtā, kur R3 ir alkilgrupa, labāk metilgrupa vai etilgrupa un R4 ir alkilgrupa, labāk metilgrupa, etilgrupa, propilgrupa vai butiigrupa, vislabāk R4 ir metilgrupa. Labāk R3 un R4 ir metilgrupa.(2) In the above-mentioned group (A), which is preferred, and in the preferred group and belonging to the group (A), the group of compounds which is preferred above is where R 3 is alkyl, preferably methyl or ethyl and R4 is alkyl, preferably methyl, ethyl, propyl or buty, preferably R4 is methyl. Preferably R3 and R4 are methyl.

[0087] (3) Iepriekš minētajā (A) grupā, kurai dodama priekšroka, un grupā, kurai priekšroka dodama pirmām kārtām un kura pieder pie (A) grupas, savienojumu grupa, kurai priekšroka dodama pirmām kārtām,'ir tā, kur R3 un R4 kopā ar oglekļa atomu, pie kura tās pievienotas, veido cikloalkilēnu, labāk ciklopropilēnu, ciklopentilēnu vai cikloheksilēnu, vēl labāk ciklopropilēnu.(3) In the above-mentioned group (A), which is preferred, and in the group which is preferred, and which belongs to group (A), the group of compounds which is preferred above is' where R3 and \ t R4 together with the carbon atom to which they are attached form cycloalkylene, preferably cyclopropylene, cyclopentylene or cyclohexylene, more preferably cyclopropylene.

[0088] (4) Iepriekš minētajā (A) grupā, kurai dodama priekšroka, un grupā, kurai priekšroka dodama pirmām kārtām un kura pieder pie (A) grupas, -savienojumu grupa, kurai priekšroka dodama pirmām kārtām, irtā, kur R3 un R4 kopā ar oglekļa atomu, pie kura tās pievienotas, veido piperidin-4-ilgrupu, kurā slāpekļa atoms aizvietots aretilgrupu, 2,2,2-trifluoretilgrupu vai ciklopropilgrupu, tetrahidropiran-4-ilgrupu, tetrahidrotiopiran-4- ilgrupu vai 1,1-dioksotetrahidrotiopiran-4-ilgrupu.(4) In the above-mentioned group (A), which is preferred, and in the preferred group, which belongs to group (A), the group of compounds which is preferred is where R3 and R4 are preferred. together with the carbon atom to which they are attached forms a piperidin-4-yl group in which the nitrogen atom is substituted with an arethyl group, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or 1,1-dioxotetrahydrothiopyran. -4-long group.

[0089] (i) Iepriekš minētajās (A) un A( 1 -4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkiigrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifluoretilgrupa, 1,1,2,2,2-pentafluoretilgrupa, 1,1,2,2,3,3,3-heptafluorpropilgrupa un R7 un RB ir ūdeņradis.(I) In the above-mentioned groups (A) and A (1 -4), which are preferred, and in groups which are preferred, and belonging to those groups, the group of compounds which is preferred is wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1,1,2,2,3,3,3-heptafluoropropyl, and R7 and RB is hydrogen.

[0090] (ii) Iepriekš minētajās (A) un A(1 -4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras'pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkiigrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R7 ir haloalkiigrupa, labāk trifluormetilgrupa, 2,2,2-trifluoretilgrupa vai 1,1,2,2,2-pentafluoretilgrupa un R8 ir ūdeņradis.(Ii) In the above-mentioned groups (A) and A (1 -4), which are preferred, and in groups which are preferred, and which belong to the above groups, the group of compounds which is preferred is: where R 6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R 7 is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2 , 2,2,2-pentafluoroethyl and R 8 are hydrogen.

[0091] (iii) Iepriekš minētajās (A) un A(1~4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka'dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur Rs ir haloalkiigrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa; R7 ir alkilgrupa, labāk metilgrupa, etilgrupa vai propilgrupa un R8 ir ūdeņradis. 16 [0092] (iv) ] (iii) Iepriekš minētajās (A) un A(1-4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kura pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkiigrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R7 ir haloalkiigrupa, labāk trifluormetilgrupa vai 2,2,2-trifluoretilgrupa un R8 ir arilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim RĒ. Labāk R8 ir fenilgrupa, 4- fluotfenilgrupa, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- vai 3,5-difiuorfenilgrupa. Vēl labāk R6 un R7 ir trifluormetilgrupa un R8 ir fenilgrupa, 4-fluorfenilgrupa, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 vai 3,5- difiuorfenilgrupa.(Iii) In the above-mentioned (A) and A (1 ~ 4) groups, which are preferred, and in groups which are preferred first and foremost, the group of compounds which is preferred is: wherein R8 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl; R7 is alkyl, preferably methyl, ethyl or propyl, and R8 is hydrogen. 16 (iv)] (iii) In the above-mentioned (A) and A (1-4) groups, which are preferred, and in the groups which are preferred, the group of compounds having preference is above all is where R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl and R 8 is aryl optionally substituted with one, two or three R 6. Better R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-diphenorphenyl. More preferably, R 6 and R 7 are trifluoromethyl and R 8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 or 3,5-diphenorphenyl.

[0093] (iv) Iepriekš minētajās (A) un A(1-4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkiigrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifluoretilgrupa vai 1,1,2,2,3- pentafluoretilgrupa, R7 ir alkilgrupa, labāk metilgrupa vai etilgrupa, un R8 ir arilgrupa, ko pēc izvēlēs aizvieto ar vienu, divām vai trim Re. Labāk R8 ir fenilgrupa, 4-fluorfenilgrupa, 2.3- , 2,4-, 2,5-, 2,6-, 3,4-vai 3,5-difluorfenilgrupa. Vēl labāk R6 ir trifluormetilgrupa un R7 ir metilgrupa un R8 ir fenilgrupa, 4-fluorfenilgrupa, 2,3-, 2.4- , 2,5-, 2,6-, 3,4,- vai 3,5-difluorfenilgrupa.(Iv) In the above-mentioned (A) and A (1-4) groups, which are preferred, and in groups that are preferred, the group of compounds that is preferred is that wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,3-pentafluoroethyl, R7 is alkyl, preferably methyl or ethyl, and R8 is aryl which is optionally substituted by one, two or three Re. Better R8 is phenyl, 4-fluorophenyl, 2.3, 2,4, 2,5, 2,6, 3,4 or 3,5-difluorophenyl. More preferably, R 6 is trifluoromethyl and R 7 is methyl and R 8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, - or 3,5-difluorophenyl.

[0094] (v) Iepriekš minētajās (A) un A(1-4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkiigrupa, labāk trifluormetilgrupa, difluormetilgrupa, 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R' ir ūdeņradis un R8 ir arilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Rs. Labāk R8 ir fenilgrupa, 4-fluorfenilgrupa, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- vai 3,5-difluorfenilgrupa. Vēl labāk R·6 ir trifluormetilgrupa un R8 ir fenilgrupa, 4- fluorfenilgrupa, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- vai 3,5-difluorfenilgrupa, labāk 2,4-difluorfenilgrupa.(V) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and belonging to the above groups, the group of compounds which is preferred is where R6 is haloalkyl, preferably trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R 'is hydrogen and R8 is aryl optionally substituted with one, two or three Rs . Better R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl. Even more R 6 is trifluoromethyl and R 8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, - or 3,5-difluorophenyl, preferably 2 , 4-difluorophenyl.

[0095] (vi) Iepriekš minētajās (A) un A(1-4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras .pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkiigrupa, labāk trifluormetilgrupa 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R7 ir haloalkiigrupa, labāk trifluormetilgrupa vai 2,2,2-trifluoretilgrupa un R8 ir heteroarilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Re. Labāk R8 ir indol-5-ilgrupa, benzoksazol-5-ilgrupa, tiofēn-3-ilgrupa, tiofēn-2-ilgrupa, furān-2-ilgrupa, piridin-4-ilgrupa, piridin-3-ilgrupa, piridin-2-ilgrupa, imidazol-5-ilgrupa, pirimidin-2- ilgrupa, pirazīn-2-ilgrupa, pirīmidin-5-ilgrupa, pirimdin-4-ilgrupa, piridazin-4-ilgrupa, izoksazol-4-ilgrupa, imidazol-2-ilgrupa, [1.2.3]tiadiazol-4-ilgrupa, imidazol-4-ilgrupa, pirazol-4-ilgrupa, tiazol-2-ilgrupa, pirazol-4-ilgrupa, pirol-2-ilgrupa, pirol-3-ilgrupa, tiazol-4-ilgrupa, tiazol-5-ilgrupa, ko neobligāti aizvieto ar vienu vai dīvām metilgrupām.(Vi) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and which are attached to said groups, the preferred group of compounds is: where R6 is haloalkyl, preferably trifluoromethyl group 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl and R8 is heteroaryl optionally optional replaced by one, two or three Re. Better R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl , imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [ 1.2.3] Thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiazole-4 long group, thiazol-5-yl optionally substituted with one or two methyl groups.

[0096] (vii) Iepriekš minētajās (A) un A(1-4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras 17 17 LV 13669 pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, irtā, kur R5 ir haloalkilgrupa, labāk trifluormetilgrupa 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R7 ir alkilgrupa, labāk metilgrupa vai etilgrupa un R8 ir heteroarilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Re. Labāk R8 ir indol-5-ilgrupa, benzoksazol-5-ilgrupa, tiofen-3-ilgrupa, tiofen-2-ilgrupa, furan-2-ilgrupa, piridin-4-ilgrupa, piridin-3-ilgrupa, piridin-2-ilgrupa, imidazol-5-ilgrupa, pirimidin-2- ilgrupa, pirazin-2-ilgrupa, pirimidin-5-ilgrupa, pirimdin-4-ilgrupa, piridazin-4-ilgrupa, izoksazol-4-ilgrupa, imidazol-2-ilgrupa, [1.2.3]tiadiazol-4-ilgrupa, imidazol-4-ilgrupa, pirazol-4-ifgrupa, tiazol-2-ilgrupa, pirazol-4-ilgrupa, pirol-2-ilgrupa, pirol-3-ilgrupa, tiazol-4-ilgrupa, tiazol-5-ilgrupa, ko neobligāti aizvieto ar vienu vai divām metilgrupām.(Vii) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and which belong to those groups, the group of compounds which is preferred to the first group where R5 is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is alkyl, preferably methyl or ethyl, and R8 is heteroaryl optionally substituted by one, two or three Re. Better R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl , imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [ 1.2.3] Thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrole-3-yl, thiazole-4 long group, thiazol-5-yl optionally substituted with one or two methyl groups.

[0097] (viii) Iepriekš minētajās (A) un A(1-4) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai priekšroka dodama pirmām kārtām, ir tā, kur R6 ir haloalkilgrupa, labāk trifluormetilgrupa 2,2,2-trifluoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R7 ir ūdeņradis un R8 ir heteroarilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Re Labāk R8 ir indol-5-ilgrupa, benzoksazol-5-ilgrupa, tiofen-3-ilgrupa, tiofen-2-ilgrupa, furan-2-ilgrupa, piridin-4-ilgrupa, piridin-3-ilgrupa, piridin-2-ilgrupa, imidazol-5-ilgrupa, pirimidin-2-ilgrupa, pirazin-2-ilgrupa, pirimidin-5-ilgrupa, pirimdin-4-ilgrupa, piridazin-4-ilgrupa, izoksazo!-4-ilgrupa, imidazol-2-ilgrupa, [1.2.3]tiadiazol-4-ilgrupa, imidazol-4-ilgrupa, pirazol-4-ilgrupa, tiazol-2-ilgrupa, pirazol-4-ilgrupa, pirol-2-ilgrupa, pirol-3-ilgrupa, tiazo!-4-ilgrupa, tiazoI-5-ilgrupa, ko neobligāti aizvieto ar vienu vai divām metilgrupām, [0098] (a) Iepriekš minētajās (A); A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām ' kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, irtā, kur R5 ir cikloalkilalkilgrupa, kas neobligāti aizvietota ar vienu, divām vai trim Rā, kas neatkarīgi izvēlētas no alkilgrupas vai halogēna vai Rc, kas izvēlēta no aralkilgrupas vai heteroaralkilgrupas, labāk 1-metilciklopentilmetilgrupas, l-metilcīkloheksilmetilgrupas, 1-metilciklobutilmetilgrupas, 1-metil-3,3-difluorciklobutilmetilgrupas, 1 -metil-4,4-difluorcikloheksilmetilgrupas, 1 -benzil-ciklopropiletilgrupas, 1-tiazoi-2-ilmetilciklopropilmetilgrupas vai 1 -metiI-3,3-difluorciklopentilmetilgrupas.(Viii) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and belonging to said groups, the group of compounds that is preferred is where R6 is haloalkyl, preferably trifluoromethyl group 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is hydrogen and R8 is heteroaryl optionally substituted with one, two or three Re Better R8 is indole -5-long group, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, imidazol-5 -yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2.3 ] thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiazol-4-yl, thiazol-5-yl optionally substituted by one or di methyl groups, (a) above (A); In groups A (1-4), A (i-viii) and A (1-4) (i-viii), which are preferred, and in groups that are preferred to the first order, and belonging to said groups, the group of compounds, preferred, where R 5 is cycloalkylalkyl optionally substituted with one, two or three R 8 independently selected from alkyl or halogen or R c selected from aralkyl or heteroaralkyl, preferably 1-methylcyclopentylmethyl, 1-methylcyclopentylmethyl, 1-methylcyclopentylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclohexylmethyl, 1-Methylcyclobutylmethyl, 1-methyl-3,3-difluoro-cyclobutylmethyl, 1-methyl-4,4-difluoro-cyclohexylmethyl, 1-benzylcyclopropylethyl, 1-thiazol-2-ylmethylcyclopropylmethyl, or 1-methyl-3,3-difluoro-cyclopentylmethyl.

[0099] (b)) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(i-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 ir alkilgrupa, labāk 2,2-dimetilpropilgrupa, 3,3-dimetilpentilgrupa, 2,2,3,3- tetrametilbutilgrupa.(B)) Preferred groups (A), A (1-4), A (i-viii) and A (i-4) (i-viii) above and groups preferred first and foremost of these groups, the more preferred group of compounds is where R5 is alkyl, preferably 2,2-dimethylpropyl, 3,3-dimethylpentyl, 2,2,3,3-tetramethylbutyl.

[0100] (c)) Iepriekš minētajās (A), A( 1 -4), A(i-viii) un A(i-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, irtā, kur R5 ir haloalkilgrupa, labāk 2,2-dihloretilgrupa, 3,3,3-trifluorpropilgrupa, 2,2- trifluormetiletilgrupa vai 2,2,2-trifluoretilgrupa.(C)) Preferred groups (A), A (1 -4), A (i-viii) and A (i-4) (i-viii) above and groups preferred first and foremost of these groups, a group of compounds having even greater preference is wherein R5 is haloalkyl, preferably 2,2-dichloroethyl, 3,3,3-trifluoropropyl, 2,2-trifluoromethylethyl or 2.2, 2-trifluoroethyl.

1S1S

[0101] (d)) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 ir haloalkifgrupa, kas aizvietota ar arilgrupu, heteroarilgrupu vai heterocikloalkilgrupu, labāk 2,2-difluor-3-fenilpropilgrupu, 2,2-difluor-3-ietrahidropirān-4-ilpropilgrupu, 2,2-difluor-3-morfolin-4-ilpropilgrupu, 2,2-difluor-3-piridin-2-ilpiOpilgrupu, 2,2-difluor-3-piridin-3-ilpropilgrupu vai 2,2-dihlor-3-fenilpropilgrupu.(D)) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above and preferred groups first and foremost of these groups, the more preferred group of compounds is where R5 is haloalkoxy substituted with aryl, heteroaryl or heterocycloalkyl, preferably 2,2-difluoro-3-phenylpropyl, 2,2- difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholin-4-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpentyl, 2,2-difluoro-3-pyridin-3-yl ilpropyl or 2,2-dichloro-3-phenylpropyl.

[0102] (e)) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, irtā, kur R5 īraralkilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Ra, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hīdroksilgrupas, haloalkoksigrupas, ciānogrupas vai halogēna; vai neobligāti aizvieto ar vienu vai divām Rb, kas neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēts no hidroksialkilgrupas, alkoksialkilgruas, aminoalkilgrupas, arilgrupas, heteroarilgrupas, aralkilgrupas, neteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgrupas, heierocikloalkilgrupas, heterocikloalkilalkilgrupas, acilgrupas, ariloksikarbonilgrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, ariloksigrupas, heteroariioksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarboniigrupas, aminosulfonilgrupas vai -S02R11 (kurR11 iralkilgrupa, cikloalkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa); un, arī, kur aromātisko vai aliciklisko gredzenu Rc neobligāti aizvieto ar vienu, divām vai trim Rd, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas vai halogēna. Labāk R5 ir benzilgrupa, 4-metoksibenzifgrupa, 3,4-dihlorbenzilgrupa, 2-hlorbenzilgrupa, 4-etoksibenzilgrupa, bifen-4-ilmetilgrupa, naft-1-ilmetilgrupa, naft-2-ilmetilgrupa, 4-hlorbenzilgrupa, 3-hlorbenzilgrupa, 4-fluorbenzilgrupa, 2-fenetilgrupa, 4-hidroksibenzilgrupa, 2-(4-hidroksifeniljetilgrupa, 2,6-difluorbenzilgrupa, bifenil-3-ilmetilgrupa, 3-fenilpropilgrupa vai 2,2-dimetil-3-fenilpropilgrupa. Labāk R3 ir 2-hlorbenzilgrupa, 3-hlorbenzilgrupa vai 4-fluorbenzilgrupa.(E)) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred first and foremost of these groups, a group of compounds having an even greater preference is wherein R5 is an arylalkyl optionally substituted by one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halogen; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, neteroaryl, arylalkyl , cycloalkyl, cycloalkylalkyl, heierocikloalkilgrupas, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, aryloxy, heteroariioksigrupas, aralkyloxy, heteroaralkiloksigrupas, aminokarboniigrupas aminosulfonyl or -S02R11 (kurR11 iralkilgrupa, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and also wherein the aromatic or alicyclic ring Rc is optionally substituted by one, two or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen. Better R5 is benzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 2-chlorobenzyl, 4-ethoxybenzyl, biphen-4-ylmethyl, naphth-1-ylmethyl, naphth-2-ylmethyl, 4-chlorobenzyl, 3-chlorobenzyl, 4 fluorobenzyl, 2-phenethyl, 4-hydroxybenzyl, 2- (4-hydroxyphenyljetyl, 2,6-difluorobenzyl, biphenyl-3-ylmethyl, 3-phenylpropyl or 2,2-dimethyl-3-phenylpropyl. Preferably R3 is 2-chlorobenzyl) , 3-chlorobenzyl or 4-fluorobenzyl.

[0103] (f) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 ir heteroaralkilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Rs, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas, ciānogrupas vai halogēna; vai neobligāti aizvieto ar vienu vai divām Rb, kas neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēta no hidroksialkilgrupas, alkoksialkilgrupas, aminoalkilgrupas, arilgrupas, heteroarilgrupas, . 19 19 LV 13669 aralkilgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgmpas, heterocikloafkilgrupas, heterocikloalkilalkilgrupas, acilgrupas, ariloksikarbonilgrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, ariloksigrupas, heteroariioksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonilgrupas vai -S02R11 (kurR11 ir alkilgrupa, arilgrupa, heteroarilgrupa vai heterocikioalkilgrupa); un, arī, kur aromātisko vai alicikfisko gredzenu Rc neobligāti aizvieto ar vienu, divām vai trim Rd, kas neatkarīgi izvēlētas no alkiigrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas vai halogēna. Labāk R5 ir 2- bromtiofēn-5-ilmetilgrupa, piridin-4-ilmetilgrupa vai 2l2-dimetii-3-piridin-3-iipropilgrupa.(F) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above and groups that are preferred first and those belonging to said groups, the more preferred group of compounds is where R5 is a heteroaralkyl optionally substituted with one, two or three Rs independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano or halogen; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl,. 19 19 EN 13669, aralkyl, heteroaralkyl, cycloalkyl, cikloalkilalkilgmpas, heterocikloafkilgrupas, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroariioksigrupas, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -S02R11 (kurR11 is alkyl, aryl, heteroaryl, or heterocikioalkilgrupa ); and also wherein the aromatic or alicyclic ring Rc is optionally substituted by one, two or three Rd independently selected from an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a haloalkoxy group or a halogen. Preferably R5 is 2-bromo-thiophen-5-ylmethyl, pyridin-4-ylmethyl or 2-dimethyl-3-pyridin-3-ylpropyl.

[0104] (g)) iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 -(alkilēn)-S(0)2-R9, kur R9 ir alkilgrupa, labāk R5 ir metiisulfonilmetilgrupa, etilsulfonilmetiigrupa, propil-1-sulfonilmetilgrupa, 2- metiipropiisulfoniimetiigrupa, 2-metil-sulfonileiilgrupa vai 2-etiisulfonileiilgrupa.(G) the preferred (A), A (1-4), A (i-viii) and A (1-4) (i-viii) groups preferred and in groups preferred first and foremost of these groups, the more preferred group of compounds is where R5 - (alkylene) -S (O) 2-R9, wherein R9 is alkyl, preferably R5 is methylsulfonylmethyl, ethylsulfonylmethyl, propyl 1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methylsulfonyl or 2-ethylsulfonyl group.

[0105] (h)) iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(ī-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēi lielāka priekšroka, irtā, kurR3 ir-(a!kilēn)-S(0)2'R9, kurR9 ir arilgrupa vai araikiigrupa, ko neobligāti aizvieto ar vienu, divām vai trim Ra, kas neatkarīgi izvēlētas no alkiigrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas, ciānogrupas vai halogēna; vai neobligāti aizvieto ar. vienu vai divām Rb, kās neatkarīgi izvēlētas no ūdeņraža, alkiigrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas, halogēna,' karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēts no hidroksiaikilgrupas, alkoksialkiigrupas, aminoaikiigrupas, arilgrupas, heteroariigrupas, aralkilgrupas, heteroaraikilgrupas, cikloalkilgrupas, cikloalkilalkilgmpas, heterocikloaikilgrupas, heterocikloalkilalkilgrupas, acilgrupas, ariloksikarboniigrupas, aralkiioksikarboniigrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, ariloksigrupas, heteroariioksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonilgrupas vai -S02R11 (kur R11 ir alkilgrupa, arilgrupa, heteroarilgrupa vai heterocikioalkilgrupa); un, arī, kur aromātiskais vai aiicikliskais gredzens Rc irneobligāti aizvietots ar vienu, divām vai trim Rd, kas neatkarīgi izvēlētas no alkiigrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas vai halogēna. Labāk R5 ir 2-difluormetoksifeniimetānsulfonilmetjlgrupa, 2-fenilsulfonīletilgrupa, 4-fluorfenilmetānsulfonilmetilgrupa, 4- amokarbonilfenilmetānsulfonilmetilgrupa, 4-piperazin-1-i!feni!metānsu!fonilmetiigrupa, 2-fluorfenilmetānsuifoni!metil-grupa, 3-fluorfenilmetānsulfonilmetilgrupa, 2,4,6- trifluorfenilmetānsulfonil-metilgrupa, 2-, 3- vai 4-trifluormetilfenilmetānsulfonilmetilgrupa, fenilmetānsulfonilmetilgrupa, 2-(2-,3- vai 4-trifluormetilfenil)sulfoniletilgrupa vai 2-(2-,3- vai 4-fluorfenil)sulfonileti!grupa. 20 [0106] (i)) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 ir -(alkilēn)-S(0)2-R9, kur R9 ir heteroarīlgrupa vai heteroaralkilgrupa, ko neobligāti aizvieto ar vienu, divām vai trim Ra, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas, ciānogrupas vai halogēna; vai neobligāti aizvieto ar vienu vai divām Rb, kas neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēts no hidroksialkilgrupas, alkoksialkilgrupas, aminoaikiigrupas, arilgrupas, heteroarilgrupas, aralkilgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgrupas, heterocikloalkilgrupas, heterocikioalkilalkilgrupas, acilgrupas, ariloksikarbonilgrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heieroaralkiloksikarbonilgrupas, ariloksigrupas, heteroariloksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonilgrupas vai -SO2R11 (kurR11 ir alkilgrupa, arilgrupa, heteroarīlgrupa vai heterocikloalkilgrupa); un, arī, kur aromātiskais vai alicikliskais gredzens Rc neobligāti ir aizvietots ar vienu, divām vai trim R°, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas vai halogēna. Labāk R° ir piridin-2-ilmetānsulfonilmetilgrupa, piridin-3-ilmetānsulfonilmetilgrupa, piridin-4-ilmetānsulfonilmetilgrupa, 3-difluormeioksipiridin-2-ilmetānsulfonilmetilgrupa, 2-difluormetoksipiridin-3-i!meiānsulfoniimeiilgrupa, 4- difiuormeihoksipiridin-3-ilmetānsulfonilmetiigrupa, 3-difluormetoksipiridin-4-ilmetānsulfonilmetilgrupa, pirīmidin-2-ilmeiānsulfonilmeiilgrupa, pirimidin-5-ilmetānsulfonilmetilgrupa, 3-trifluormetilpiridin-2- ilmetānsulfonilmetilgrupa, 4-trifluormetiIpirīdin-3-iImetānsulfonilmetiigrupa, 3,5-dimetilizoksazol-4-.ilmetānsulfonilmetilgrupa, 2-fiuorfurān-5-ilmetānsulfonifmetilgrupa, 2-metiltiazol-4- ilmetānsulfonilmetilgrupa, furān-2-ilmetānsulfonilmetilgrupa, 2-piridin-2-iletānsulfonilmetilgrupa, 2-piridin-3-iletānsulfonilmetilgrupa, 2-piridin-4-iletānsulfoniimetiigrupa, 2-piridin-3-i!sulfoniletilgrupa, 2-piridin-4-ilsulfoniletilgrupa, 3-piridin-3-ilsulfonilpropilgrupa, 1,3, 5-triazin-2-ilmetānsulfonilmetilgrupa, 1 ,3 ,4-tiadiazol-2-ilmetānsulfonilmetilgrupa, oksazol-5- ilmetānsulfonilmetilgrupa, tiazol-5-ilmetānsuIfonilmetilgrupa vai tiazol-2-ilmetānsulfonilmetilgrupa.(H)) preferred groups (A), A (1-4), A (i-viii), and A (1-4) (viii) above, and groups preferred first and foremost of these groups, a group of compounds having a greater preference for lysis is wherein R 3 is - (alkyl) -S (O) 2 R 9, wherein R 9 is an aryl group or an aryl group optionally substituted by one, two or three Ra independently selected from an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a haloalkoxy group, a cyano group or a halogen; or optionally replaced by. one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, cycloalkyl, cycloalkyl, aralkyl, heteroaryl, cycloalkyl, cikloalkilalkilgmpas, heterocikloaikilgrupas, heterocycloalkylalkyl, acyl, ariloksikarboniigrupas, aralkiioksikarboniigrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroariioksigrupas, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -S02R11 (wherein R11 is alkyl, aryl, heteroaryl, or heterocikioalkilgrupa); and also wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three Rd independently selected from an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a haloalkoxy group or a halogen. Better R5 is 2-difluoromethoxyphenimethanesulfonylmethyl, 2-phenylsulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylmethane, methylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethanesulfonylmethyl, 2.4.6 trifluorophenylmethanesulfonylmethyl, 2-, 3- or 4-trifluoromethylphenylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, 2- (2-, 3- or 4-trifluoromethylphenyl) sulfonethyl or 2- (2-, 3- or 4-fluorophenyl) sulfonyl group. 20 (i)) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred preferred and belonging to said groups, the more preferred group of compounds is where R5 is - (alkylene) -S (O) 2-R9, wherein R9 is a heteroaryl or heteroaralkyl optionally substituted with one , two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaralkyl , cycloalkyl, cycloalkylalkyl, heterocycloalkyl heterocikioalkilalkilgrupas, acyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heieroaralkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -SO2R11 (kurR11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and also wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three R 0 independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen. More preferably R ° and pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 4-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3- difluoromethoxypyridin-4-ylmethanesulfonylmethyl, pyrimidin-2-ylmethanesulfonylmethyl, pyrimidin-5-ylmethanesulfonylmethyl, 3-trifluoromethylpyridin-2-ylmethanesulfonylmethyl, 4-trifluoromethylpyridin-3-ylmethanesulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl, 2-fluoromethanesulfonylmethyl, 2-fluoromethan-5-ylmethanesulfonylmethyl; -ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-4-ylethanesulfonylmethyl, 2-pyridin-3-ylsulfonylmethyl, 2-Pyridin-4-ylsulfonyl-ethyl, 3-pyridin-3-ylsulfonylpropyl, 1,3,5-triazin-2-ylmethanesulfonylmethyl, 1,3,4-thiadiazol-2-expression thanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl or thiazol-2-ylmethanesulfonylmethyl.

[0107] 0) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 ir -(alkilēn)-S(0)2-R9, kur R9 ir heterocikloalkilgrupa vai heterocikloalkilalkilgrupa, kas neobligāti aizvietotas ar vienu, divām vai trim Ra, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas, ciānogrupas vai halogēna; vai neobligāti aizvieto ar vienu vai divām Rb, kas neatkarīgi izvēlētas no ūdeņraža, alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloaikoksigrupas, halogēna, karboksilgrupas vai alkoksikarbonilgrupas un vienu Rc, kas izvēlēts no hidroksialkilgrupas, alkoksialkilgrupas, aminoaikiigrupas, arilgrupas, heteroarilgrupas, 21 21 LV 13669 aralkilgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkiialkilgrupas, heterocikloalkilgrupas, heterocikloalkilalkilgrupas, acilgrupas, ariloksikarboniigrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, ariloksigrupas, heteroariloksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonilgrupas vai -SO2R11 (kur R11 iralkilgrupa, cikloalkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa); un, arī, kur aromātiskais vai alicikliskais gredzens Rc ir neobligāti aizvietots ar vienu, divām vai trim Rd, kas neatkarīgi izvēlētas no alkilgrupas, haloalkilgrupas, alkoksigrupas, hidroksilgrupas, haloalkoksigrupas vai halogēna. Labāk R5 ir piperidin-1-ilsulfonilmetilgrupa vai piperidin-4-ilmetānsulfonilmefilgrupa, kur slāpekļa atoms piperidīna gredzenā aizvietots ar metilgrupu, etilgrupu, aoetilgrupu, metilsulfonilgrupu vai aminosulfonilgrupu, tetrahidropirān-4-ilsulfonilmetilgrupu, fetrahidropirān-4-ilsulfonifmetilgrupu, 1,1-dioksotetrahidrotiopirān-4-ilmetānsulfonilmetilgrupu vai morfolin-4-ilmetānsulfonilmetilgrupu.0) Preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii) above, and groups that are preferred above and belonging to said groups, the more preferred group of compounds is where R5 is - (alkylene) -S (O) 2-R9, wherein R9 is heterocycloalkyl or heterocycloalkylalkyl optionally substituted with one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, 21 21 LV 13669, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, ariloksikarboniigrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -SO2R11 (wherein R11 iralkilgrupa, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl) ; and also wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen. Better R5 is piperidin-1-ylsulphonylmethyl or piperidin-4-ylmethanesulfonylphenyl, where the nitrogen atom in the piperidine ring is substituted with methyl, ethyl, azoethyl, methylsulfonyl or aminosulfonyl, tetrahydropyran-4-ylsulfonylmethyl, fetrahydropyran-4-ylsulfonylmethyl, 1,1-dioxotetrahydrothiopyran; 4-ylmethanesulfonylmethyl or morpholin-4-ylmethanesulfonylmethyl.

[0108] (k) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, savienojumu grupa, kurai dodama vēl lielāka priekšroka, ir tā, kur R5 ir -(alkilēn)-S(0)2-R8, kur R9 ir cikloalkilalkilgrupa, labāk R5 ir ciklopropilmetilsulfonilmetilgrupa.(K) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred first and those belonging to said groups, the more preferred group of compounds is where R5 is - (alkylene) -S (O) 2-R8, wherein R9 is cycloalkylalkyl, preferably R5 is cyclopropylmethylsulfonylmethyl.

[0109] (1) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, R5 ir etilsulfonilmetilgrupa, 2- metilsulfoniletilgrupa, 2-metillpropilsulfonilmetilgrupa, benzolsulfonilmetil, 2- fenilsulfonilletilgrupa, naft-2-ilmetānsulfonilmetilgrupa, bifenil-2-ilmetānsulfonilmetilgrupa, bifenil-4-ilmetānsulfonilmetiIgrupa, īenilmetānsulfonilmetilgrupa,-2-fenilmetānsulfoniletiJgrupa, 4-terc-butilfenilmetānsulfonilnetilgrupa, 2-fluorfenilmetānsulfonilmetilgrupa, 3-fluorfenilmetānsulfoniimetilgrupa, 4-fluorfenilmetānsulfonī!metilgrupa, 2-hlorfenilmetānsulfonilmetilgrupa, 3-hlorofenilmetānsu!foni!metilgrupa, 4-hlorfenilmetānsulfonilmetilgrupa, 2-metoksifenilmetānsulfonilmetilgrupa, 4-metoksifenilmetānsulfonilmetilgrupa, 2-trifiuormetoksifenilmetānsulfonilmetil-grupa, 3-trifluormetoksifeni!metānsulfonilmetilgrupa, 4-trifluormetoksifenil-metānsulfonilmetilgrupa, 2-trifluormetilfenilmetānsulfonilmetilgrupa, 3-trifluormetilfenilmetānsulfonilmetilgrupa, 4-trifluormetilfenilmetān-sulfonilmetilgrupa, 2-ciānofenilmetānsulfonilmetilgrupa, 3-ciānofenil-metānsulfonilmetilgrupa, 2-bromfenilmetānsulfonilmetilgrupa, 2- metilfenil-metānsuifonilmetilgrupa, 3-metilfenilmetānsulfonilmetilgrupa, 4-metilfenilmetānsulfonilmetilgrupa, 2-(4-trifluormetoksibenzolsulfonil)etilgrupa, 2-(3-trifluormetoksibenzolsulfonil)etilgrupa, 2-(2-trifluormetoksi- . benzolsulfonil)etilgrupa, 2-difluormetoksifenil-metānsulfoniletilgrupa, 3-difluormetoksifenilmetānsulfonilmetilgrupa, 4-difluormetoksifeni(metānsu!foni(-metilgrupa, 2-(4~difluormetoksībenzolsu!fonil)etilgrupa, 2-(2-difluormetoksi-benzolsulfonil)etilgrupa, 2-(3-difluormetoksibenzolsulfonil)etilgrupa, 3-hlor-2-fluorfenilmetānsulfonilmetiigrupa, 3,5-dimetilfenilmetānsuifoniimetilgrupa, 3,5-bis-trifluormetilfenilmetānsulfonilmetilgrupa, 2,5-difiuorfenilmetān-sulfonilmetilgrupa, 2,6-difluorfenilmetānulfoniImetilgrupa, 2,3-difluorfenii- 22 metānsulfonilmetilgrupa, 3,4-dīfluorfenilmetānsulfonīlmetilgrupa, 2,4-difiuorfenilmetānsulfoniimetilgrupa, 2,5-dihlorfenilmetānsulfonilmetilgrupa, 3,4-dihlorfenilmetānsulfonilmetilgrupa, 2,6-dihlorfenilmetānsulfonilmetiigrupa, 2-fluor-3-meiilfenilmetānsūlfonilmetilgrupa, 4-fluor-2-trifluormetoksifenil-metānsulfonilmeiilgrupa, 2-fluor-6-iiifluormetilfenilmetānsulfonilinetilgrupa, 2-fluor-3-triilūormeiilfenilmeiānsulfonilmetilgrupa, 2-fluor-4-trifluormetilfenil-metānsulfonilmetilgrupa, 2-fluor-5-trifluormetilfenilmetānsulfoniimetilgrūpa, 4-flūor-3-trifluormetilfenilmetānsulfonilmetilgrupa, 2-hlor-5 trifluormetilfenil-metānsulfonilmetilgrupa, 2,4,6-triflūorfenilmetānsulfonilinetilgrupa, 2,4,5-trifluorĪeniimetānsulfonilmetūgrupa, 2,3,4-trifluorfenilinetānsulfonilmetilgrupa, 2,3,5-trifluorfenīlmetānulfonilmetilgrupa, 2,5,6-trifluorfenilmetānsulfonil-metilgrupa, 3,4,5-trimetoksifenilmeiānsulfonilmetilgrupa, piridin-2-ilmetānsulfonilmetilgrupa, piridin-3 -ilmetānsulfonHmeiūgrupa, piridin-4-il-metānsulfonilmetilgrupa, 2-(piridin-2-ilsūlfonil)eiilgrupa, 2-(piridin-4-ilsu!fonil)etilgrupa, oksipiridin-2-ilmetānsulfonilmeiilgmpa, cikloheksilmetānsulfanilmetilgrupa, cikloheksilmetānsulfonilmetilgrupa, ciklopropilmetānsulfonilmetilgrupa, iiofēn-2-sūlfonilmetilgrupa, 5-hlorotiēn-2-ilmetānsulfonilmetilgrupa vai 3,5-dimeiilizoksazol-4-ilmetānsulfoni!meii]grupa.(1) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred belonging to the mentioned groups, R5 is ethylsulfonylmethyl, 2-methylsulfonylmethyl, 2-methylpropylsulfonylmethyl, benzenesulfonylmethyl, 2-phenylsulfonylmethyl, naphth-2-ylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, -2-phenylmethanesulfonylmethyl, -2-phenylmethanesulfonylmethyl, 4-tert-butilfenilmetānsulfonilnetilgrupa, 2-fluorfenilmetānsulfonilmetilgrupa, 3-fluorfenilmetānsulfoniimetilgrupa, 4-fluorfenilmetānsulfonī! methyl 2-hlorfenilmetānsulfonilmetilgrupa, 3-hlorofenilmetānsu! backgrounds! methyl 4-hlorfenilmetānsulfonilmetilgrupa, 2-metoksifenilmetānsulfonilmetilgrupa, 4-metoksifenilmetānsulfonilmetilgrupa, 2-trifiuormetoksifenilmetānsulfonilmetil-group 3-Trifluoromethoxyphenylmethanesulfonylmethyl, 4-trifluoromethoxyphenylmethane fonilmetilgrupa, 2-trifluormetilfenilmetānsulfonilmetilgrupa, 3-trifluormetilfenilmetānsulfonilmetilgrupa, 4-trifluormetilfenilmetānsulfonilmetilgrupa, 2-ciānofenilmetānsulfonilmetilgrupa, 3-ciānofenilmetānsulfonilmetilgrupa, 2-bromfenilmetānsulfonilmetilgrupa 2- methylphenyl metānsuifonilmetilgrupa-3-metilfenilmetānsulfonilmetilgrupa, 4-metilfenilmetānsulfonilmetilgrupa, 2- (4-trifluormetoksibenzolsulfonil ) ethyl, 2- (3-trifluoromethoxybenzenesulfonyl) ethyl, 2- (2-trifluoromethoxy-. benzenesulfonyl) ethyl, 2-difluoromethoxyphenylmethanesulfonyl-ethyl, 3-difluoromethoxyphenylmethanesulfonylmethyl, 4-difluoromethoxyphen (methanesulfones (methyl, 2- (4-difluoromethoxybenzenesulfonyl) ethyl, 2- (2-difluoromethoxybenzenesulfonyl) ethyl, 2- ( 3-Difluoromethoxybenzenesulfonyl) ethyl, 3-chloro-2-fluorophenylmethanesulfonylmethyl, 3,5-dimethylphenylmethanesulfonylmethyl, 3,5-bis-trifluoromethylphenylmethanesulfonylmethyl, 2,5-difluorophenylmethanesulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl, 2,3-difluorophenyl-22-methanesulfonylmethyl, , 3,4-Diphenylphenylmethanesulfonylmethyl, 2,4-difluorophenylmethanesulfonylmethyl, 2,5-dichlorophenylmethanesulfonylmethyl, 3,4-dichlorophenylmethanesulfonylmethyl, 2,6-dichlorophenylmethanesulfonylmethyl, 2-fluoro-3-methylphenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxyphenylmethanesulfonylmethyl, 2 -fluoro-6-fluorofluoromethylphenylmethanesulfonylmethyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2- fluoro-4-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl, 4-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2,4,5-trifluoromethylmethanesulfonylmethyl, , 3,4-Trifluorophenylmethanesulfonylmethyl, 2,3,5-trifluorophenylmethanesulfonylmethyl, 2,5,6-trifluorophenylmethanesulfonylmethyl, 3,4,5-trimethoxyphenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-yl Methanesulfonylmethyl, 2- (pyridin-2-ylsulfonyl) -yl, 2- (pyridin-4-ylsulfonyl) ethyl, oxypyridin-2-ylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclopropylmethanesulfonylmethyl, 5-chlorothene-2-sulfonylmethyl, 5-chlorothiene-2 -ylmethanesulfonylmethyl or 3,5-dimethylisoxazol-4-ylmethanesulfonyl] group.

[0110] (m) Iepriekš minētajās (A), A(1-4), A(i-viii) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, R° ir 1-etoksikarboni[piperidin-4-ilmeĪiigrupa, 1-metilpiperidin-4-ilmetilgrupa, 2-teirahīdropirām-4-iletilgrupa, pirolidin-1 -ilmetilgrupa, piperidin-1 -ilmetilgrupa, morfolin-4-ilmetilgrupa, 2-morfolin-4-iletilgrupa, tiomorfolin-4-iletilgrupa, 1-okso-tiomorfolin-4-iimeiilgrupa, 1,1 -dioksotiomorfolin-4-ilmetilgrupa, teirahidroiiopirān-4-ilmeiilgrupa, 1-oksotetrahidrotiopirān-4-ilmetilgrupa, 1,1-dioksoteirahidrotiopirān-4-ilmeiilgrupa, 1-metilpiperazin-4-ilmeĪilgrupa, benziloksimetilgrupa, etoksimetilgrupa, izopropiloksimetilgrūpa, 2-piperia'in-1-iletilgrupa, 2-pirolidin-1-iletilgrupa, terc-butiloksimetilgrupa, imidazol-4-ilmetilgrupa, indol-3-iimeiilgrupa, indol-2-ilmetilgrupa, 1-benzilimidazol-4-ilmetilgrupa; 4-etil-4-metilpiperidin-1 -ilmetilgrupa, indol-1 -ilmetilgrupa, 1-metilpiperidin-2-ilmetilgrupa, 2,2,-difluor-3-tiēn-2-ilmetilgrupa vai piridin-4-ilmetilgrupa.(M) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups that are preferred first belonging to the groups mentioned, R ° is 1-ethoxycarbonone [piperidin-4-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-teirahydropyram-4-yl-ethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholine -4-ylmethyl, 2-morpholin-4-yl-ethyl, thiomorpholin-4-yl-ethyl, 1-oxo-thiomorpholin-4-ylamyl, 1,1-dioxothiomorpholin-4-ylmethyl, tertiary hydropyran-4-ylmethyl, 1-oxotetrahydrothiopyran-4 -ylmethyl, 1,1-dioxoteirahydrothiopyran-4-ylmeyl, 1-methylpiperazin-4-ylmeyl, benzyloxymethyl, ethoxymethyl, isopropyloxymethyl radical, 2-piperidin-1-yl-ethyl, 2-pyrrolidin-1-ylethyl, tert-butyloxymethyl, imidazole 4-ylmethyl, indol-3-ylamyl, indol-2-ylmethyl, 1-benzylimidazol-4-ylmethyl; 4-ethyl-4-methylpiperidin-1-ylmethyl, indol-1-ylmethyl, 1-methylpiperidin-2-ylmethyl, 2,2, -difluoro-3-thien-2-ylmethyl or pyridin-4-ylmethyl.

[0111] (n) Iepriekš minētajās (A), A(1-4), A(ī-viīi) un A(1-4)(i-viii) grupās, kurām dodama priekšroka, un grupās, kurām priekšroka dodama pirmām kārtām un kuras pieder pie minētajām grupām, R5 ir 3,5-dimetilizoksazol-4-ilmetānsulfonilmetilgrupa, 2-CF3meti!fenilmetān-sulfonilmetilgrupa, 3-CF3piridin-2- ilmetānsulfonilmetilgrupa, 2-F-furān-5-ilmetānsulfonilmetilgrupa, 2-metiltiazol-4- ilmetānsulfonilmetilgrupa, tetrahidropirān-4-ilmetānsulfonilmetilgrupa, 1,1-diokso-1A6-heksahīdrotiopirān-4-ilmetānsulfonilmetilgrupa, 1-etilpiperidin-4-ilmetānsulfonilmetilgrupa, 2-oksotetrahidropirimidin-4-ilmetān-sulfonilmetilgrupa, 1-etil-2-oksopiperidin-4-ilmetānsulfonilmetilgrupa, 1-acetilpiperidin-4-ilmetānsulfonilmetilgrupa, 1-etoksikarbonilpiperidin-4-ilmetānsulfonilmetilgrupa, 1-metilsulfonilpiperidin-4-ilmetānsulfonilmetilgrupa, 1 -ciklopropilpiperidin-4-ilmetānsulfonilmetilgrupa, 1-acetilazetidin-3-ilmetānsulfonilmetiigrupa, 1-etoksikarbonilazetidin-3-ilmetānsulfonilmetilgrupa, 1-metīlsulfonilazetidin-3- ilmetānsulfonilmetilgrupa, 1-etilazetidin-3- 23 23 LV 13669 ilmetānsulfonilmetilgrupa, 1-ciklopropilazetidin-3- ilmetānsulfonilmetilgrupa, furān-2-ilmetānsulfonilmetilgrupa, difluor-(4-f)uorfenil) metānsulfonilmetilgmpa, difiuor-(pirazin-2-il)metānsulfonilmetilgrupa, difluor-(2-difluormetoksifenil metānsulfonilmetilgmpa, 1-acetilpiperidin-4-i)sulfonilmetilgrupa, 1-etoksikarbonilpiperidin-4- ilsulfonilmetilgrupa, 1 -ciklopropilpiperidin-4-ilsulfonilmetilgrupa, 2-(piridin-2- il)etānsulfonilmetilgrupa, 2-(piridin-3-il)etānsulfonilmetilgrupa, 2-(pīridin-4-il)etānsulfonilmetilgrupa, 3-(piridin-2-iljpropānsulfonilmetilgrupa, 2,6-difluorfenilmetānsulfonilgrupa, [1,3.5]triazin-2-ilmetānsulfonilmetilgrupa, [1.3.4]tiadiazol-2-ilmetānsulfonilmetilgrupa, oksazol-5- ilmetānsulfonilmetilgrupa, tiazol-5-ilmetānsulfonilmetilgrupa, 4-fluorfenilmetānsulfonilmetilgrupa, 4-aminokarbonilfenilmetānsulfonil-metilgrupa, 4-piperazin-4-ilfenilmetānsulfonilmetilgrupa, 5-fluorindo(-3-ilmetānsulfonilmetilgrupa, 4,6-difluorindol-3-ilmetānsulfonilmetilgrupa, 1- metilindol-3- ilmetānsulfonilmetilgrupa, 4-fluorindol-3-ilmetānsulfonilmetilgrupa, 2-(5- fluorindoi-3-il)etānsulfonilmetilgrupa, 2-(4,6-difluorindol-3-i!)etānsulfonilmetilgrupa, 2-(1-metilindol-3-il)etānsulfonilmetilgrupa, 2-(4-f!uorindo!-3-ii)etānsulfonilmetilgrupa, 2-hinolin-3-ileiānsulfonilmetilgrupa, 2-hino!in-2-iletānsulfonifmetilgrupa, izohinolin-3-ilmetānsulfoniimetilgrupa, 2-(izohinolin-3-il)etānsu!fonilmetilgrupa, 2,4-difluorpiridin-3-ilmetānsulfonilmetilgrupa, 3,4-difluorpiridin-4-ilmetānsulfonilmetilgrupa, 2-(2,4-difluorpiridin-3-il)etānsulfonilmetilgrupa, 2-(3,4-difluorpindin-4-ii}etānsulfonilmetilgrupa, fluor-(^^-difluorpiridin-S-iOmetānsulfonilmetilgrupa, fluor-(3,4-difluorpiridin-4-il)metānsuifonilmeiilgrupa, 2,4-diCF3piridin-3-ilmetānsulfonilmetilgrupa, 3,4-diCF3piridin-4-ilmetānsulfonilmetilgrupa, 2-(2,4-diCF3piridin-3-il)etānsulfonilmetilgrupa, 2-(3,4- diCF3piridin-4-il)etānsuIfonilmetilgrupa, fluor-(2,4-diCF3piridin-3-il)meiānsulfonilmetilgrupa, fluor-(3 ,4-diCF3p!ridin-4-ii)metānsulfonilmetilgrupa, 4-F-piridin-3-ilmetānsuifonilmetilgrupa, 3-F-piridin-5-ilmetānsulfonilmeiilgrupa, 2-F-piridin-5-ilmetānsulfonilmetilgrupa, 2-"F-piridin-3- ilmetānsulfonilmetilgrupa, 5-F-piridin- 2- ilmetānsulfonilmetilgrupa, 4-F-piridin-2- ilmetānsulfonilmetilgrupa, 4-F-1 -oksopiridin-3-ilmetānsulfonilmetilgrupa, 3-F-1-oksopiridin-5-ilmetānsulfonilmetilgrupa, 2-F-1-oksopiridin-5-ilmetānsulfonilmetilgrupa, 2-F-1-oksopiridin-3- ilmetānsulfonilmetilgrupa, 5-F-1-oksopiridin-2-ilmetānsulfonilmetilgrupa, 4-F-1 -oksopiridin-2-ilmetānsulfonilmetilgrupa, 4-CF3-piridin-2-ilmetilsulfonilmetilgrupa, 3-CF3-piridin-5-ilmetānsulfonmetilgrupa, 3- F-piridin-2-ilmetānsulfonilmetilgrupa, 2-CF3-piridin-3-ilmetānsulfonilmetilgrupa, 4-CF3-1 -oksopiridin-2- ilmetānsulfonilmetilgrupa, 3-CF3-1-oksopridin-5-īlmetānsulfonilmetilgrupa, 3- F-1-oksopiridin-2-ilmetānsulfonilmetilgrupa, 2-CF3-1-oksopiridin-3-ilmetānsulfonilmetilgrupa, 5-CF3-1-oksopiridin-2-ilmetānsulfonilmetilgrupa, 2-CH3-pīridjn-6-ilmetānsulfonilmetilgrupa, 3-CH3-piridin-2-ilmetānsulfonīlmetilgrupa, 4-CH3-piridin-3-ilmetānsulfonilmetilgrupa, 3-CH3-piridin-4-ilmetānsulfonilmetilgrupa, 2- (2-CFt3-piridin-6-il)etānsulfonilmetilgrupa, 2-(3-CF3-piridin-2-il)etānsulfonilmetilgrupa, 2-(4-CF3-piridin-3-il) etānsulfonilmetilgrupa, 2-(3-CF3-piridin-4-il)etānsulfonilmetīlgrupa, 2-C2H5-pindin-6-ilmetānsulfonilmetilgrupa, 3- C2H5- piridin-2-ilmetānsulfonilmetilgrupa, 4-C2Fl5-piridin-3-ilmetānsulfonilmetilgrupa, 3-C2H5- piridīn-4-ilmetānsulfonīlmetilgrupa, 2-(2-C2Fl5-piridin-6-il)etānsuffonilmetilgrupa, 2-(3-C2H5-piridin-2-il)etānsu!fonilmetilgrupa, 2-(4-C2Fl5-p!ridin-3-il)etānsulfoni!metilgmpa, 2-(3- 24 C2H5-pindin-4-il)etānsulfoniimet!lgrupaJ 2-(2-CH3-piridīn-3-il)etānsulfonilmetilgrupa, 2-CF3-piridin-3-ilmetānsulfonilmetilgmpa1 2-(3-CF3-piridin-4-i[)etānsulfonilmetilgrupa, 3-CF3-piridin-4-ifmetānsu!foniimetĪlgrupa, cinnolin-3-ileiānsuifonilmetilgrupa, 2-(cinnolin-3-il)etānsuifonilmetilgrupa, ftalazin-1- ilmetānsuffonilmetilgrupa, 2-(ftalazin-1-il)etānsūifonilmeiilgrupa, 2-(hnoksa!in-2-il)etānsuIfonilmetilgrupa, hinazolin-2-ilmetānsulfonilmetilgmpa, 2-(hinazofin-2-il)efānsulfonil,etilgrupa, [1,8]nafiiridin-2-ilmetānsulfonilmetilgrupa, 2-( [1,8]naftiridin-2- i!)etānsulfoniimeiilgrupa, [1,8]naftiridin-3-ilmetānsulfonilmetilgrupa, 2-( [1,8]naftiridin-3-il)etānsulfonilmetilgrupa, 3-CI-piridin-2-ilmetānsulfonilmetilgrupa, 4-CI- piridin-3- ilmetānsulfonilmetilgrupa, 3-CI-piridin-4-ilmetānsūlfonūmetilgrupa, 3-F-piridi.n-2-ilmeiānsulfonilmetilgrupa, 4-F-piridin-3-ilmetānsuIfonifmetiigrupa1 3-F-piridin-4- ilmetānsulfonilmetilgrupa, izohinoiin-4-iimetānsulfonilmetilgrupa, 6-fenilpiridin-2-ilmeiānsulfoni[-metilgrupa, 3-feni[piridin-2-i[meiānsulfonilmeti!grupa, 4-fenilpiridin-2-ilmetānsulfonilmetiigrupa, 3-fenilpiridin-4-ilmetānsūlfonilmetilgrupa, 2-(6-fenilpiridin-2-il)etānsulfonilmetiigrupa, 2-(3-fenilpiridin-2-il)eiānsuifoniJmeti!grupa, 2-(4-feniipiridin-3-il)eiānsulfonilmetiigrupa, 2-(3-fenilpiridin-4-il)etānsulfonilmeiilgrupa, 6-(piridin-2-i[)piridin-2-ilmetānsuifonilmeĪilgnJpa, 3-(piridin-2-il)piridin-2-ilmeiānsu!foni!metilgmpa, 4-(piridin-2-il)pindin-3-i!meiānsulfonilmetilgrupa, 3-(piridin-2-il)piridīn-4-i[metānsulfonilmetilgrupa, 2-[6-(piridin-2-il)pindin-2-i[]etānsulfonilmetilgrupa, 2-[3-(piridin-2-il)piridin-2-iljetānsulfonilmetilgrupa, 2-[4-(piridin-2-il)piridin-3-īi]etānsulfoniimeiilgrupa, 2-[3-(pirid!n-2-!!)piridin-4-il]eiānsulfonilmetilgrupa, 6-(piridin-3-il)piridin-2-ilmetānsuifonilmetilgrupa, 3-(piridin-3-il)piridin-2-i[meĪānsulfonilme{ilgrupa, 3-(pindin-3-il)pindin-3-ilmetānsulfonilmetilgrupa, 3-(piridin-3-il)piridin-4-ilmetānsulfonilmetilgrupa, 2-[6-(piridin-3-!l)piridin-2-il]eiānsuffonilmetilgrupa, 2-[3-(piridin-34l)piridin-24l]etānsulronilmetiigrupa, 2-[4-(piridin-3-il)piridin-2-iljetānsulfonilmetilgrupa, 2-[3-(piridin-3-il)piridin-4-il]eiānsulfonilmetilgrupa, 6-(pindin-4-il)piridin-2-ilmetānsūlfoni!metilgrupa, 3-(piridin-4-ii)piria'in-2-ilmetānsulfonilmetilgrupa, 4-(piridin-4-il)piridin-3-ilmetānsulfonilmsti]grupa1 3-'(piridin44l)piYidin-44lmetānsulfonilmeiilgrupa, 2-[6-(piridin-4-i[)piridin-2-il]etānsulfonilmeiilgrupa, 2-[3-(piridin-4-il)piridin-2-i!]etānsulfoni!metilgrupa, 2-[4-(pīridin-4-ii)piridin-3-ii]etānsulfonīImetilgrupaI 2-[3-(piridin-4-il)piridin-4-il]etānsulfonilmetilgrupa, 2,2-dimetilciklopropilmetānsulfonilgrupa, bifen-2-ilmetānsulfonilgrupa, 2- tiofen-2-iIfenilmetānsulfonilgrupa, 2-tiazol-2-iifenilmetānsulfonilgrupa, 2-tiazol-5-ilfenilmetānsulfonilgrupa, 2-[1.2.3]tīadiazol-5-ilfenilmetānsulfonilgrupa, 2-īzoksazol-5-ilfenilmetānsulfonilgrupa, 2-(1 -metilpirazol-5-il)fenilmetānsulfonilgrūpa, 2-[1.2.3]triazol-5-ilfenilmetānsu!fonilgrupa, 2- [1.2.3]oksadiazol-5-iifenilmeiānsulfoniigrupa, 2-[(1.2.3)triazo!-5-il]fenilmetānsulfonilgmpa, 2-[(1.2.3)triazol-1 -iljfenilmetānsulfonilgrupa, oksazoio[5,4-b]piridin-2-ilmetānsulfonilmetilgrupa, oksazolo[4,5-c]piridin-2-ilmetānsulfonilmeti!grupa, oksazolo[4,5-b]piridin-2-ilmeiānsu[fonilmetilgrupa, benzimidazol-5-ilmetānsulfonilmetilgrupa, benzimidazo!-4- ilmetānsulfonilmetilgrupa, 3H-imidazo[4,5- b]piridin-2-ilmetānsulfonilmetilgrupa, 3H'imidazo[4,5-c]piridin-2-ilmetānsulfonilmetilgrupa, 3-CF3-3H-imidazo[4,5-b]pirīdin-2-ilmetānsulfonilmetilgrupa,3-CF3-3H-īmidazo[4,5-c]pirīdin-2- · ilmetānsulfonilmetilgrupa, 25 25 LV 13669 1- CF3-1FMrnidazo[4,5-c]piridin-2-ilmetānsulfonilmetiIgrupa, I-CF3-IH-imidazo[4,5-b] piridin-2-iImetānsulfonilmetilgrupa, tiazo![5,4-b]piridin-2-ūmetānsulfonilmetilgrupa, tiazol[4,5-c]pindin-2-ilmetānsulfonilmetilgrupa, tiazol[4,5-b]piridin-2-ilmetānsulfonilmetilgrupa, 5- CF3tiazoi[534-b]piridīn-2-(]metānsuifoniImetiIgrupa, 4-CF3-tiazol[4,5-c]piridin- 2- ilmetānsulfonilmeii[grupa,7-CF3“tiazol[4,5-b]piridin-2-ilmetānsulfonilmetilgrupa, 3- CF3-1 H-piroJ[233-b]piridīn-2-ilmetānsulfonifmetilgrupa, 3-CF3-1 H-pirol[3,2-c]piridin-2-iimetānsūlfoniimetīigrupa,3-CF3-1 H-p/rol[3,2-b]piridin-2-ilmetānsulfonilmetilgrupa, imidazo[1 ,2-cJpirimkiin-2-metānsulfonilmetilgrupa, 8-CF3-imidazo [1,2-c] pirimidin-2-metānsulfonilmeiilgmpa, imidazo[1,2-a]pirimidin-2-metānsulfonilmetilgrupa, 8-CF3-imidazo[1,2-b] piridazin-2-metānsulfonilmetilgrupa, imidazo[1J2-a]pirazin-2-metānsulfoni[metilgrupa, 8-CFs-imidazofl.ž-ajpirazin^-metānsulfonilmetilgrupa, pirazol[1,5-c]pirimidin-2-ilmetānsulfonilmetilgrupa, 3-CF3-pirazol[1 ,5-c]pirimidin-2-ilmetānsulfonilmetilgrupa, 4-CF3-pirazo![1,5-c]pirimidin-2-ilmetānsuifoniirnetilgrupa, imidazo[1,2-d] [1,2,4]triazin-2-meiānsulfonilmetilgrupa, 3-CF3-imidazo[1,2-d] [1,2,4]triazin-2-meiānsulfonilmetilgrupa, [1.3] benzoksazol-2- ilmetānsuifonilmetilgrupa, 5-F-[1,3]benzoksazoi-2-ilmetānsuifonilmeiilgrupa, [1,3]benzoksazol-4-ilmetānsulfonilmetilgrupa, 2-CF3- [1,3]benzoksazol-4-ilmetānsulfon!!meiilgrupa, [1,3]benzoksazol-7-ilmetānsulfonilmetilgrupa, 2-CF3-[1,3]benzoksazol-7-ilmetānsulfonilmetilgrupa, [1 ,2jbenzoksazoI-3- ilmetānsuifonilmetilgrupa. [1,2]benzoksazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-[1,2]benzoksazol-4-ilmetānsuifonilmetiigrupa, 3-CF3-[1,2]benzoksazol-4-ilmefānsu[foni[meti(grupa, 6-CF3-[1,2]benzoksazol-7- ilmetānsuifonilmetilgrupa, 6-CN-[1,2]benzoksazol-7-ilmēīānsulfonilmetilgrupa, '3-CF3-[1,2]benzoksazol-7-. ilmetānsuifonilmetilgrupa, 5-F-[1,2]benzoksazol-3-ilmetānsulfonilmetilgrupa, [2.3] benzoksazol-7- ilmetānsuifonilmetilgrupa, 6-CF3-[2,3]benzoksazol-7-ilmetānsulfonilmetīlgrupa, 1-CF3- [2,3]benzoksazol-7-ilmetānsulfonilmetilgrupa, 5-CF3-[2,3]benzoksazol-4 -ilmetānsuifonilmetilgrupa, 5- CN-[2,3]benzoksazoI-4-ilmetānsulfonilmetilgrupa, 1-CF3-[2,3]benzoksazoI-4-ilmetānsulfonilmetilgrupa, benzotiazol-2-ilmetānsuifonilmetilgrupa, 5-F-benzotiazol-2-ilmetānsulfonilmetilgrupa, benzotiazol-4-ilmetānsulfonilmetilgrupa, 2-CF3-benzotiazol-4-ilmetānsulfonilmetilgrupa, benzotiazol-7-ilmetānsulfonilmetilgrupa, 2-CF3-benzotiazol-7-ilmetānsulfonilmetilgrupa, [1 ,2]benzotiazol-3-ilmetānsulfonilmetilgrupa, [1,2] benzotiazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-[1,2]benzotiazol-4-ilmetānsulfonilmetīlgrupa, 3-CF3-[1,2] benzotiazol-4-ilmetānsulfonilmetilgrupa, 6- CF3-[1,2]benzotīazol-7-ilmetānsulfonilmetilgrupa, 6-CN-[1,2]benzotiazol-7-ilmetānsulfonilmetilgrupa, 3 -CF3- [ 1,2]benzotiazol-7-ilmetānsulfonilmetīlgrupa, 5-F-[1,2]benzotiazol-3-ilmetānsulfonilmetilgrupa, [2,3]benzotiazol-7-ilmetānsulfonilmetilgrupa, 6-CF3- [2,3]benzotiazol-7-ilmetānsulfonilmetīlgrupa, 1-CF3-[2,3] benzotiazol-7-ilmetānsulfonilmetilgrupa, 5'CF3-[2,3]benzotiazol-4-ilmetānsiilfonilmetilgrupa, 26 5-CN-[2,3]benzotiazol-4-i!metānsulfonilmeti[grupa, 1-CF3-[2,3]benzotiazol-4-ilmetānsūlfonilmetilgrupa,4-CF3-2-CH3-tiazol-5-ilmetānsulfonilmetilgrupa, 4-CF3-tiazol-5-ilmeĪānsulfonilmetilgrupa, 4-CF3-2-feniI-tiazol-5-ilmetānsulfonilmetilgrupa, 5-CF3-2-CH3-tiazol-4-ilmetānsulfoni[metilgrupa, 5-CF3-2-feni!-tiazol-4-ī!metānsulfonilmetilgrupa, 5-CH3- tiazol-2-ilmetānsulfonilmetilgrupa, 5-CF3- tiazol-2-iimetānsulfonilmetilgrupa, 5-fenil-tiazol-2-ilmeiānsulfonilmetilgrupa, 4-CH3-tiazol-2-ilmetānsulfonilmetilgrupa, 4 CF3-tiazol-2-ilmetānsu]fonilmetilgrupa,4-fenil-tiazo!-2-ilmetānsulfonilmetilgrupa, 5-CH3-2-(piridin-2-ii)-[1,233]triazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-2-(pindin-2-iI)-[1,2,3]ίπ3ζοΙ-4-ilmetānsulfonilmeiilgrupa 5-CF3-2-(4-metilsulfonilfeni!)-[1,2,3]triazol-4-Hmetānsulfonilrnetilgrupa, 4,5-dimeti!-[1,2,4]triazol-3-ilmetānsulfoni!metilgriipa, 5-CF3-4-CH3- [1.2.4] iriazo!-3-ilmeiānsuifonilmetilgrupa, 4-CH3-5-fenil-[1,2,4]triazol-3-ilmstānsulfonilmetilgrupa, 5- CF3-4-ciklopropil-[112,4]tr!azol-3-ilmetānsū!fonilmetilgrupa, 2,5-dimetil- [1.2.4] triazol-3-ilmetānsulfoni!meiilgrūpa, 5-CF3-2-CH3-[1,2,4]triazol-3-ilmetānsulfonilmeiilgrupa, 2- CFl3-5-fenil-[1,2l4]triazol-3-ilmeiānsūlfonilmetilgrūpal 2-cik!opropil-5-feniI- [1.2.4] inazo!-3-i!meiānsūlfonilmetiigrupa, 5-CF3-1 -CHS-[1 ^.^ļiriazol-S-ilmetānsulfonilmetilgrupa, 1 -CH3-5-fenil-[1,2,4]trīazol-3-iJmetānsulfonilmetiJgrupa, 5-CH3-1 -fenīl- [1.2.4] iriazol-3-ilmetānsulfon!lmeiilgrupa, 3-CH3-[1,2,4]oksadiazoi-5-Hmetānsulfonilmetilgrupa, 3-CF3-[1,2,4]oksadiazol-5-timeĪānsulfoni!rneĪilgrupa S-fenil-fl^^joksadiazoi-S-ilmeiānsuifonilmetilgrupa, 5-CH3[1,2,4]oksadiazo!-3-iImetānsulfonilmetilgrupa, 5-CF3-[1,2,4]oksadiazoi- 3- ilmetānsulīonilmetilgrupa, 5-fenil-[1,2,4]oksadiazol-3-ūmetānsulfonilmetilgrupa, 2-CH3-[1,3,4]oksadiazoI-5- ilmetānsulfoniimetilgrupa, 2-CF3-[1,3,4]oksadiazol-54lmetānsuIfonilmeiilgrupal 2- fenil-[1,3,4]oksadiazol-5-ilmeiānsulfonilmeĪilgrupa, 3-CH3- [1,2,4]iiadiazol-5-ilmetānsulfonilmetilgrupa, S-CFrfl^^ļiiadiazoI-S-ilmetānsūlfonilmetilgrupa, 3- feni!-[1 ^^tiadiazoI-S-ilmetānsuifonīlmetilgrupa.S-CHa-fl ,2,4]tiadīazol-5-ilmeiānsulfonilmetifgrupa, 5-CF3-[1 ,2,4]tiadiazol-3-Hmetānsulfoniirneiilgrupa, 5-fenil-[1,2,4]tiadiazol-3-ilmetānsulfonilmetiigrupa, 2- CH3-[1 ,3,4]iiadiazoi-5-ilmetānsulfonilmeĪi!grupa, 2-CF3-[1,3,4]tiadiazol-5-ilmetānsulfonilmetilgrupa, 2-fenil-[1,3,4]iiadiazol-5-ilmeiānsulfonilmetilgrupa, 2,2-difluorpirolidinilmetānsulfonilmetilgrupa, 3,3-difluorpirolidinilmetānsulfonilmetilgrupa, 3- CF3-N-CH3-pirol-2-ilmetānsulfonilmetilgrūpa, 3-CN-N-CH3-pirol-2-ilmetānsulfonilmetilgrupa, 4- CF3-N-CH3-pīrol-2-ilmeiānsulfonilmetilgrupa, 4-(1 -CH3-1 - hidroksietil)-N-CH3-pirol-2-ilmetānsulfonilmetilgrupa, 1,3-dimetilpirol-2-ilmetānsulfonilmetilgrupa, 4-CF3-N-CH3- pirol-3-ilmetānsulfonilmetilgmpa, 4-CN-N-CH3-pirol-3-ilmetānsūlfonilmetiIgrupa, 4-CN-N-(3J3,3-trifluorpropil)-pirol-3-ilmetānsulfonilmetilgrupaI 2-CF3-N-CH3-pirol-3-īlmetānsuIfonilmetiIgmpa, 2-CF3-N-fenil-pirol-3-ilmetānsulfonilmetilgrupa, 4-CF3-pirol-2-iimetānsūlfonilmetilgrupa, 4-(1 -CH3-1-hidroksieiil)-pirol-2-ilmetānsulfoniImetilgrupa, 27 27 LV 13669 3-CH3-pirol-2-ilmetānsulfonilmetilgrupa, 4-CF3-pirol-3-ilmetānsulfonilmetilgrupa, 2-CF3-piro!'2-ilmetānsulfonilmetilgrupa, 3-CF3-pirol- 2- ilmetānsulfonilmeiilgrupa, 2-CF3-pirol-4-!lmetānsulfonilmeĪilgmpa, 2~CF3-N-CH3-pirol-4-ilmetānsulfonilmetilgrupa, 3- CF3-fūr-2H'lmetānsulfonilmeti!grupa, 3-CN-fur-2-ilmetānsulfonilmetilgrupa, 3-CF3-fur-4-ilmetānsulfonilmetilgrūpa, 3-CN-fur'4-ilmetānsulfonilmetilgrupa, 2-CF3-fur-3-ilmetānsulfonilmeti!grupa, 3'CF3- tiazol-2-ilmetānsulfonilmetilgrupa, 3-CN-tiazol-2-ilmetānsulfonilmetilgrupa; 3-CF3- tiazol-4-ifmetānsulfonilmetilgrupa, 3-CN-tiazol-4-ilmetānsulfonilmetilgrupa, 2-CF3-tiazol-3-iimetānsulfonilmetiIgrupa, N-CFl3-3-CF3-1H-pirazol-5-ilmetānsulfonilmetilgrupa, N-CH3-3-(1 -CH3-1 -hidroksietil)-1 H-pirazoī-5-ilmetānsulfoniimetīlgrupa, N-CH3-3-fenil-1 Fl-pirazol-5-ilmetānsuffonilmeiilgrupa, N-CH3-3-CF3-1H-pirazof-4-ilmetānsulfoniimetilgrupa, N-CH3-4-CN-1H- pirazol-3-ilmetānsulfonilmetilgrupa, N-fenil-4-CN-1H- pirazol-3-ilmetānsulfonilmetiJgrupa, N-fenil-3-CF3-1FI-pirazol-4-ilmetānsulfonilme{i!-grupa, N-febii-5-CF3-1 H-pirazol-34lmetānsulfonilmetilgrupa, (N-CF)3-4-CF3-1Fi-imidazo!-2- ilmetānjsulfonilmetilgrupa, [N- CH3-4-(1-CH3-1-hidroksietiI)-1H-imidazo!-2- iimetānjsuifonilmetilgrupa, (N-CH3-4-fenil-1 H-imidazol-2-ilmetān)sulfonilmetilgrupa1 N-CH3-3-CF3-I H-pirazol-4-ūmetānsulfonilmetilgmpa, (N-CH3-2-CF3-1H-imidazo!-5- iimetānjsuifonilmetilgrupa (N-CH3-2-feni!-1 FI-imidazol-5-ilmetān)sulfonilmetilgrupa, (N-CH3-5-CF3- 1H-imidazol-4-ilmetān)sulfonilmetilgrupa; (N-fenil-5-CF3- 1H-imidazol-5-ilmetān)sulfonilmetilgrupa, 4-CN-[1,2]oksazoi-5-iimetānsulfoniimetilgrupa, 4-CN-3-fenil-[1,2]oksazol-5-iimetānsulfonilmetilgrupa, 4-CN-[1,2]oksazol-3-ilmetānsulfoni[metilgrupa, 4-CN-5-fenil-[1,2]oksazol-3-i(metānsulfonilmetilgrupaI 4-CN-izotiazol-5-ilmetānsulfoniimetilgrupa, 4-CN-3-fenīl-izotiazoI-5-iimetansulfoniimetiIgrupa, 4-CN-izotiazol-5-ilmetānsulfonilmetilgrupa, 4-CN-5-fenil-izotiazol-3-ilmetānsuIfoniimetilgrupa, 4-CF3-[1 ,2]oksazol-5-ilmetānsulfonilmetilgrupa, 4-CF3-3-CH3-[1,2]oksazol-5-iImetānsulfoniimetiigrupa, 4-CF3-3-fenil-[1,2]oksazo!-5-ilmetānsulfoni!metilgrupa, 4-CF3-[1,2]oksazol-3-ilmetānsuifonilmetiigrupa, 4-CF3-5-CH3-[1,2]oksazol-3-iimetānsuifonilmetilgrupa, 4-CF3-5-fenil-[1,2]oksazol-3-ilmetānsulfonilmetiigrupa, 3- CF3-[1,2]oksazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-[1,2]oksazoi-4-ilmetānsulfonilmetilgrupa, 4- CF3-[1,2]oksazol-3-ilmetānsulfoniimetiigrupa, 4-CF3-3-CFI3- [1,2]oksazol-5-ilmetānsulfonilmetilgrupa, 4-CF3-3-fenil-[1,2]oksazoi-3-ilmetānsulfonilmetilgrupa, 4-CF3-[1,2]oksazoJ-3-ilmetānsulfonilmetilgrupa, 4-CFa-S-CHs-fl^Joksazol-S-ilmetānsulfonilmetilgrupa, 4-CF3-5-fenil-[1,2]oksazol-3-ilmetānsulfonilmetilgrupa, 3-CF3-[1,2]oksazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-[1,2]oksazoI-4-ilmetānsulfonilmetilgrupa, 4-CFf3-[1,2]oksazoi-5-ilmetānsulfonilmetilgrupa, 4-CH3-3-fenil-[1,2]oksazol-5-ilmetānsulfonilmetilgrupa, 4-CH3-[1,2]oksazol-3-ilmetānsulfonilmetilgrupa, 4-CHs-S-fenil-fl^joksazoi-S-ilmetānsulfonilmetilgrupa, 28 3- CH3-[1 ^joksazoM-ilmetānsulfoniimetilgrupa, 5-CH3-[1,2]oksazol-4-ilmetānsulfonilmetilgrupa, 4- CH3-izotiazol-5-ilmetānsulfonilmetilgrupa, 4-CH3-3-fenil-izotiazo[-5-ilmetānsulfonilmetilgrupa, 4-CH3-izotiazol-3-ilmetānsūlfonilmetiigmpa, 4-CH3-5-fenil-izotiazol-3-ilmetānsulfonilmetilgrupa, 3- CH3-izotiazol-4-ilmetānsuifonilmetilgrupa, 5-CH3-izotiazol-4-ilmetānsulfonilmetilgrupa, 4- CF3-2-CH3- [1,3]oksazol-5-i!meiānsulfonilmetilgrupa, 4-CF3-[1,3]oksazol-ilmetānsulfonilmetilgrupa, 4-CF3-fenil-[1,3]oksazol-5-ilmetānsulfonilmetilgrupa, 5- CF3-2-CH3-[1,3Joksazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-[1,3]oksazol-4-ilmetānsulfonilmetilgrupa, 5-CF3-2-fenil-[1,3]oksazol-4-ilmetānsulfonilmeiilgrupa, 5-CH3-[1,3]oksazol-2-ilmetānsulfonilmeiilgrupa, 5-CFs-fl.SJoksazol^-iimetānsūlfonilmetilgrupa, 5-fenil- [1,3]oksazol-2-ilmetānsulfonilmetilgrupa, 4-CH3-[1,3]oksazol-2-ilmetānsuffonilmetilgrupa, 4-CF3-[1 ,3]oksazol4^ilmetānsulfonilmetilgrupa, 4-fenil-[1,3]oksazol-2-ilmeĪānsulfoniJmetiigrupa, N-metil-indoi-2-ilmetānsulfonilmeiilgrupa, 3-CF3-indol-2-ilmetānsulfoniimetilgrupa, 3-CF3-N-metilindol-2-ilmeiānsulfonilmetilgrupa, 5-fluoro-N-meti!indo!-2-ilmetānsulfonilmetilgrupa, N-metilindol-3-ilmeĪānsuifonilmetiJgrūpa, 2-CF3-indol-3-ilmetānsulfoniimetiigrupa, 2-CF3-N-meiilindol-3-ilmetānsu!fonilmetilgrupa, 5-fiuor-N-meti!indol-3-ilmetānsulfonilmetilgrupa, 5-CF3-N-metilindoi-4-ilmetānsūlfonilmetilgrupa, 5-CN-N-mstilindol-4-ilmeiānsūffoniimeiilgrupa, 2-CF3-N-meĪiiindo!-4-ilmetānsuifonilmeiilgrupa, 3-CF3-N-metilindol-4-ilmetānsulfonilmeiilgrupa, 6-CF3-N-meiilindol-7-!lmetānsuifoni!meii!grupa, 6-CN-N-metilindoi-7-ilmetānsulfoniimetiigrupa, 2- CF3-N-meti!indo!-7-i!metānsulfonilmeiilgrupa, 3-CF3-N-metilindoF7-iimetānsulfonilmetilgrupa, benzofurān-2-ilmetānsulfonilmetilgrupa, 3-CF3-benzofurān-2-ilmetānsulfonilmetilgrupa, 3- CN-benzofurān-2-ilmetānsulfonilmetilgrupa, 5-'F-benzofurān-2-iimetānsulfonilmetilgrupa, benzofurān-3-iimetānsulfonilmetilgrupa, 2-CF3-benzofurān-3-ilmetānsulfonilmetilgrupa, 2-CH3-benzofurān-3-ilmetānsulfonilmeiilgrupa, 5-F-benzofurān-3-ilmetānsulfonilmetilgrupa, 5- CF3-benzofurān-4-ilmeiānsulfoni!meii!grupa, 5-CN-benzofurān-4-ilmetānsulfonilmetilgrupa, 2-CF3-benzofurān-4-ilmetānsulfoni!metilgrupa, 3-CF3-benzofurān-4-ilmetānsulfonilmetilgrupa, 6- CF3-benzofurān-7-ilmetānsulfonilmetilgrupa, 6-CN-benzofurān-7-ilmefānsulfonilmetilgrupa, 2-CF3-benzofurān-7-ilmetānsulfonilmetilgrupa, 3-CF3-benzofurān-7-iJmetānsuifonilmetilgrupa, benzotiēn-2-ilmetānsuifonilmeiilgrupa, (3 -CF3-benzotiēn-2-ilmetān)suffonilmetilgrupa, 29 29 LV 13669 (S-CN-benzotiēn-Ž-ilmetānJsulfonilmetilgrupa, (5-F benzotiēn-2-ilmetān)sulfoniImetilgrupa, benzotiēn-3-ilmetānsulfonilmeĪilgrupa, (2-CF3-benzotīēn-3-ilmetān)sulfonilmetilgrupa, (2-CH3-benzotiēn-3-ilmetān)sulfonilmetilgrupa, (5-fluorbenzotiēn-3-ilmetān)sulfoni!metilgrupa, (5-CF3-benzotiēn-4-ilmetān)suifoni!metilgrupa, (5-CN-benzotiēn-4-iImetān)sulfonilmetiigrupa, (2-CF3-benzotiēn-4-iimeiān)su!fonilmetilgrupa, (3-CF3-benzotiēn-4-ilmetān)su!fonilmetilgrupa, (6-CF3- benzofiēn-7-ilmetān)sulfonilmetilgrupa, (6-CN-benzotiēn-7-ilrnetān)su(fonilmetiigrupa, (2-CF3-benzotiēn-7-ilmetān)sulfonilmetilgrupa, (3-CF3-benzotiēn-74lmetān)sulfonilmetilgrupa, N-metilbenzimidazol-2-ilrneiānsulfonilmetilgrupa, (5-fluor-N-meti[benzimidazoI-2-ilrnetānsu[fonilmetilgrupa, (N-metiiindazol-3-ilmetān)sulfonilmetilgrupa, (5-fluor-N-metilindazol-3-ilmetān)su!foniimetilgrupa, (2-CF3-N-metilbenzimidazo!-4-iimetān)sulfoniImetilgrupa, (2-CF3-N-meiilbenzimidazol-7-ilmetān)sulfonilmeii[grupa, (N-metilindazol-4-ilmetān)sulfoni[metilgrupa, (5-CF3-N-metilindazol-4-ilmetān)sulfonilmeiilgrupa, (3-CF3-N-metilindazol-4-ilmetān)sulfonilmetilgrupa, (6- CF3-N-mei!lindazo!-7-Hmetān)su[foni!metilgrupa, (6-CN-N-metilindazo!-7-ilmetān)sulfoniimetilgrupa vai (3-CF3-N-metilindazol-7-ilmetān)sLi!foni!meiilgrupa.(N) The above-mentioned (A), A (1-4), A (vi-vi) and A (1-4) (i-viii) preferred groups and first-to-first groups belonging to the mentioned groups, R5 is 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl, 2-CF3methylphenylmethanesulfonylmethyl, 3-CF3pyridin-2-ylmethanesulfonylmethyl, 2-F-furan-5-ylmethanesulfonylmethyl, 2-methylthiazolyl 4-ylmethanesulfonylmethyl, tetrahydropyran-4-ylmethanesulfonylmethyl, 1,1-dioxo-1A6-hexahydro-thiopyran-4-ylmethanesulfonylmethyl, 1-ethylpiperidin-4-ylmethanesulfonylmethyl, 2-oxotetrahydropyrimidin-4-ylmethanesulfonylmethyl, 1-ethyl-2-oxopiperidinyl 4-ylmethanesulfonylmethyl, 1-acetylpiperidin-4-ylmethanesulfonylmethyl, 1-ethoxycarbonylpiperidin-4-ylmethanesulfonylmethyl, 1-methylsulfonylpiperidin-4-ylmethanesulfonylmethyl, 1-cyclopropylpiperidin-4-ylmethanesulfonylmethyl, 1-acetyl azetidin-3-ylmethanesulfonylmethyl, 1-ethoxycarbonyl azetidin-3-ylmethyl, year n-sulfonylmethyl, 1-methylsulfonylazetidin-3-ylmethanesulfonylmethyl, 1-ethylazetidin-3-yl-23,213,139,9-methanesulfonylmethyl, 1-cyclopropylazetidin-3-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, difluoro- (4-fluorophenyl) methanesulfonylmethylgmpa, pyrazin-2-yl) methanesulfonylmethyl, difluoro- (2-difluoromethoxyphenylmethanesulfonylmethylgmpa, 1-acetylpiperidin-4-yl) sulfonylmethyl, 1-ethoxycarbonylpiperidin-4-ylsulfonylmethyl, 1-cyclopropylpiperidin-4-ylsulfonylmethyl, 2- (pyridin-2-yl) ) ethanesulfonylmethyl, 2- (pyridin-3-yl) ethanesulfonylmethyl, 2- (pyridin-4-yl) ethanesulfonylmethyl, 3- (pyridin-2-ylpropane sulfonylmethyl, 2,6-difluorophenylmethanesulfonyl, [1,3,5] triazin-2-ylmethanesulfonylmethyl) [1.3.4] Thiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-4-ylphenyl methanesulfonylmethyl, 5-fluoroindo (-3-ylmethanesulfonylmethyl, 4,6-difluorindol-3-ylmethanesulfonylmethyl, 1-methylindol-3-ylmethanesulfonylmethyl, 4-fluoroindol-3-ylmethanesulfonylmethyl, 2- (5-fluoroindol-3-yl) ethanesulfonylmethyl, 2- (4,6-Difluoroindol-3-yl) ethanesulfonylmethyl, 2- (1-methylindol-3-yl) ethanesulfonylmethyl, 2- (4-fluoroindol-3-yl) ethanesulfonylmethyl, 2-quinolin-3 -ilyansulfonylmethyl, 2-quinolin-2-ylethanesulfonylmethyl, isoquinolin-3-ylmethanesulfonylmethyl, 2- (isoquinolin-3-yl) ethanophenylmethyl, 2,4-difluoropyridin-3-ylmethanesulfonylmethyl, 3,4-difluoropyridin-4-one 2- (2,4-difluoropindin-4-yl) ethanesulfonylmethyl, fluoro (N, N-difluoropyridine-5-ylmethanesulfonylmethyl, fluoro) (3,4-difluoropyridin-5-ylmethanesulfonylmethyl); -difluoropyridin-4-yl) methanesulfonylmethyl, 2,4-diCF3-pyridin-3-ylmethanesulfonylmethyl, 3,4-diCF3-pyridin-4-ylmethanesulfonylmethyl, 2- (2,4-diCF3-pyridin-3-yl) -ethanesulfonyl Methyl, 2- (3,4-diCF3-pyridin-4-yl) ethanesulfonylmethyl, fluoro- (2,4-diCF3-pyridin-3-yl) -methanesulfonylmethyl, fluoro- (3,4-diCF3-pyridin-4-yl) -methanesulfonylmethyl, 4 -F-pyridin-3-ylmethanesulfonylmethyl, 3-F-pyridin-5-ylmethanesulfonylmethyl, 2-F-pyridin-5-ylmethanesulfonylmethyl, 2- " F-pyridin-3-ylmethanesulfonylmethyl, 5-F-pyridin-2-ylmethanesulfonylmethyl 4-F-Pyridin-2-ylmethanesulfonylmethyl, 4-F-1-oxopyridin-3-ylmethanesulfonylmethyl, 3-F-1-oxopyridin-5-ylmethanesulfonylmethyl, 2-F-1-oxopyridin-5-ylmethanesulfonylmethyl, 2-F 1-Oxopyridin-3-ylmethanesulfonylmethyl, 5-F-1-oxopyridin-2-ylmethanesulfonylmethyl, 4-F-1-oxopyridin-2-ylmethanesulfonylmethyl, 4-CF 3-pyridin-2-ylmethylsulfonylmethyl, 3-CF 3-pyridin-5 -ylmethanesulfonmethyl, 3- F-pyridin-2-ylmethanesulfonylmethyl, 2-CF 3-pyridin-3-ylmethanesulfonylmethyl, 4-CF 3 -1-oxopyridin-2-ylmethanesulfonylmethyl, 3-CF 3 -1-oxopridin-5-ylmethanesulfonylmethyl , 3- F-1-oxopyridin-2-ylmethanesulfonylmethyl, 2-CF 3 -1-oxopyridin-3-ylmethanesulfonylmethyl, 5-CF 3 -1-oxopyridin-2-ylmethanesulfonylmethyl, 2-CH 3 -pyridin-6-ylmethanesulfonylmethyl, 3-CH 3 pyridin-2-ylmethanesulfonylmethyl, 4-CH3-pyridin-3-ylmethanesulfonylmethyl, 3-CH3-pyridin-4-ylmethanesulfonylmethyl, 2- (2-CFt3-pyridin-6-yl) ethanesulfonylmethyl, 2- (3-CF3-pyridine) -2-yl) ethanesulfonylmethyl, 2- (4-CF3-pyridin-3-yl) ethanesulfonylmethyl, 2- (3-CF3-pyridin-4-yl) ethanesulfonylmethyl, 2-C2H5-Surin-6-ylmethanesulfonylmethyl, 3- C2H5 - pyridin-2-ylmethanesulfonylmethyl, 4-C2F15-pyridin-3-ylmethanesulfonylmethyl, 3-C2H5-pyridin-4-ylmethanesulfonylmethyl, 2- (2-C2F15-pyridin-6-yl) ethanephonylmethyl, 2- (3-C2H5-pyridine -2-yl) ethanophenylmethyl, 2- (4-C2F15-pyridin-3-yl) ethanesulfonylmethylgmpa, 2- (3-24C2H5-Surin-4-yl) ethanesulfonimide, 2- (2- CH3-Pyridin-3-yl) ethanesulfonylmethyl, 2-CF3-pyridin-3-ylmethanesulfonylmethyl-methyl-2- (3-CF) 3-Pyridin-4-yl) ethanesulfonylmethyl, 3-CF 3-pyridin-4-ylmethanone-phononyl, cinnolin-3-ynylfiphenylmethyl, 2- (cinnolin-3-yl) ethanesulfonylmethyl, phthalazin-1-ylmethanesulfonylmethyl, 2- (phthalazine) -1-yl) ethanephiphenylmeyl, 2- (henoxyn-2-yl) ethanesulfonylmethyl, quinazolin-2-ylmethanesulfonylmethylgmpa, 2- (quinazopin-2-yl) efanesulfonyl, ethyl, [1,8] naphthyridin-2-ylmethanesulfonylmethyl, 2- ([1,8] naphthyridin-2-yl) ethanesulfonylmethyl, [1,8] naphthyridin-3-ylmethanesulfonylmethyl, 2- ([1,8] naphthyridin-3-yl) ethanesulfonylmethyl, 3-Cl-pyridinyl 2-ylmethanesulfonylmethyl, 4-Cl-pyridin-3-ylmethanesulfonylmethyl, 3-Cl-pyridin-4-ylmethanesulfonomethyl, 3-F-pyridin-2-ylmethanesulfonylmethyl, 4-F-pyridin-3-ylmethanesulfonylmethyl-3-pyridin-3-yl-pyridine -4-ylmethanesulfonylmethyl, isoquinoin-4-methanesulfonylmethyl, 6-phenylpyridin-2-ylmethanesulfonylmethyl, 3-phenyl [pyridin-2-yl] -methanesulfonylmethyl, 4-phenylpyridin-2-ylmethanesulfonylmethyl α, 3-phenylpyridin-4-ylmethanesulfonylmethyl, 2- (6-phenylpyridin-2-yl) ethanesulfonylmethyl, 2- (3-phenylpyridin-2-yl) pyranophenylmethyl, 2- (4-phenylpyridin-3-yl) ethanesulfonylmethyl , 2- (3-Phenylpyridin-4-yl) ethanesulfonylmeyl, 6- (pyridin-2-yl) pyridin-2-ylmethanesulfonylmethylglyn, 3- (pyridin-2-yl) pyridin-2-ylidenhanesone. - (pyridin-2-yl) quinolin-3-ylmethanesulfonylmethyl, 3- (pyridin-2-yl) pyridin-4-yl [methanesulfonylmethyl, 2- [6- (pyridin-2-yl) surfin-2-one [] Ethanesulfonylmethyl, 2- [3- (pyridin-2-yl) pyridin-2-yl] sulfonylmethyl, 2- [4- (pyridin-2-yl) pyridin-3-yl] ethanesulfonylmethyl, 2- [3- (pyrid! n-2 - (pyridin-4-yl) -ansulfonylmethyl, 6- (pyridin-3-yl) pyridin-2-ylmethanesulfonylmethyl, 3- (pyridin-3-yl) pyridin-2-yl (methylsulfonylmethyl); - (Surin-3-yl) Surin-3-ylmethanesulfonylmethyl, 3- (pyridin-3-yl) pyridin-4-ylmethanesulfonylmethyl, 2- [6- (pyridin-3-yl) pyridin-2-yl] pyranphonylmethyl, 2- [3- (pyridin-34l) pyridin-24l] ethanesulronil methyl, 2- [4- (pyridin-3-yl) pyridin-2-yl] ethanesulfonylmethyl, 2- [3- (pyridin-3-yl) pyridin-4-yl] ethanesulfonylmethyl, 6- (quinolin-4-yl) pyridine -2-ylmethanulfonylmethyl, 3- (pyridin-4-yl) pyridin-2-ylmethanesulfonylmethyl, 4- (pyridin-4-yl) pyridin-3-ylmethanesulfonylmethyl] -13- (pyridin-4-yl) -pyridin-44lmethanesulfonylmethyl, 2- [6- (Pyridin-4-yl) pyridin-2-yl] ethanesulfonylmethyl, 2- [3- (pyridin-4-yl) pyridin-2-yl] ethanesulfonylmethyl, 2- [4- ( pyridin-4-yl) pyridin-3-yl] ethanesulfonylmethyl-2- [3- (pyridin-4-yl) pyridin-4-yl] ethanesulfonylmethyl, 2,2-dimethylcyclopropylmethanesulfonyl, biphen-2-ylmethanesulfonyl, 2-thiophen-2 Phenylmethanesulfonyl, 2-thiazol-2-ylphenylmethanesulfonyl, 2-thiazol-5-ylphenylmethanesulfonyl, 2- [1,2,3] thiazol-5-ylphenylmethanesulfonyl, 2-oxazol-5-ylphenylmethanesulfonyl, 2- (1-methylpyrazol-5-yl) ) phenylmethanesulfonyl radical, 2- [1.2.3] triazol-5-ylphenylmethanesulfonyl, 2- [1.2.3] oxadiazol-5-iphenylmethanesulfonyl upa, 2 - [(1.2.3) triazol-5-yl] phenylmethanesulfonylgmpa, 2 - [(1.2.3) triazol-1-yl] phenylmethanesulfonyl, oxo [5,4-b] pyridin-2-ylmethanesulfonylmethyl, oxazole [4 5-c] pyridin-2-ylmethanesulfonylmethyl, oxazolo [4,5-b] pyridin-2-ylmethanone [phenylmethyl, benzimidazol-5-ylmethanesulfonylmethyl, benzimidazol-4-ylmethanesulfonylmethyl, 3H-imidazo [4,5- b] pyridin-2-ylmethanesulfonylmethyl, 3H-imidazo [4,5-c] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-3H-imidazo [4,5-b] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-3H- ε-azazo [4,5-c] pyridin-2-ylmethanesulfonylmethyl, 2525 [deg.] 13669 1-CF3-1Frnidazo [4,5-c] pyridin-2-ylmethanesulfonylmethyl, 1-CF3-1H-imidazo [4,5-b ] pyridin-2-ylmethanesulfonylmethyl, thiazol [5,4-b] pyridin-2-methanesulfonylmethyl, thiazole [4,5-c] quinolin-2-ylmethanesulfonylmethyl, thiazole [4,5-b] pyridin-2-ylmethanesulfonylmethyl, 5-CF3-thiazole [534-b] pyridin-2 - (] methanesulfonylmethyl, 4-CF3-thiazole [4,5-c] pyridin-2-ylmethanesulfonylmethyl [group, 7-CF3] Thiazol [4,5-b] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-1H-pyrido [233-b] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-1H-pyrrolo [3,2-c] pyridine -2-methanesulfonylmethyl, 3-CF3-1H-pyrrolo [3,2-b] pyridin-2-ylmethanesulfonylmethyl, imidazo [1,2-c] pyrimidin-2-methanesulfonylmethyl, 8-CF3-imidazo [1,2-c] pyrimidin-2-methanesulfonylmethylgmpa, imidazo [1,2-a] pyrimidin-2-methanesulfonylmethyl, 8-CF3-imidazo [1,2-b] pyridazin-2-methanesulfonylmethyl, imidazo [1J2-a] pyrazin-2-methanesulfonyl [ methyl, 8-CFs-imidazofl-1-pypyrazin-4-methanesulfonylmethyl, pyrazolo [1,5-c] pyrimidin-2-ylmethanesulfonylmethyl, 3-CF3-pyrazolo [1,5-c] pyrimidin-2-ylmethanesulfonylmethyl, 4-CF3 pyrazolo [1,5-c] pyrimidin-2-ylmethanesulfonylmethyl, imidazo [1,2-d] [1,2,4] triazine-2-methanesulfonylmethyl, 3-CF3-imidazo [1,2-d] [ 1,2,4] Triazine-2-methanesulfonylmethyl, [1.3] benzoxazol-2-ylmethanesulfonylmethyl, 5-F- [1,3] benzoxazol-2-ylmethanesulfonylmethyl, [1,3] benzoxazol-4-ylmethanesulfonyl Ethyl, 2-CF 3 - [1,3] benzoxazol-4-ylmethanesulfonylmethyl, [1,3] benzoxazol-7-ylmethanesulfonylmethyl, 2-CF 3 - [1,3] benzoxazol-7-ylmethanesulfonylmethyl, [1,2] benzoxazole -3-ylmethanesulfonylmethyl. [1,2] Benzoxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,2] benzoxazol-4-ylmethanesulfonyl-ethyl, 3-CF3- [1,2] benzoxazole-4-enefan [Backgrounds (Group, 6-CF3) - [1,2] benzoxazol-7-ylmethanesulfonylmethyl, 6-CN- [1,2] benzoxazol-7-ylidenesulfonylmethyl, 3-CF3- [1,2] benzoxazol-7-ylmethanesulfonylmethyl, 5-F- [1] 2] benzoxazol-3-ylmethanesulfonylmethyl, [2.3] benzoxazol-7-ylmethanesulfonylmethyl, 6-CF3- [2,3] benzoxazol-7-ylmethanesulfonylmethyl, 1-CF3- [2,3] benzoxazol-7-ylmethanesulfonylmethyl, 5- CF3- [2,3] benzoxazol-4-ylmethanesulfonylmethyl, 5- CN- [2,3] benzoxazol-4-ylmethanesulfonylmethyl, 1-CF3- [2,3] benzoxazol-4-ylmethanesulfonylmethyl, benzothiazol-2-ylmethanesulfonylmethyl, 5 -F-benzothiazol-2-ylmethanesulfonylmethyl, benzothiazol-4-ylmethanesulfonylmethyl, 2-CF3-benzothiazol-4-ylmethanesulfonylmethyl, benzothiazol-7-ylmethanesulfonylmethyl, 2-CF3-benzothiazol-7-ylmethanesulfonylmethyl, [1,2] benzothiazol-3-yl ylmethanesulfonylmethyl, [1,2] benzothiazol-4-ylmethanesulfonylmethyl, 5-CF 3 - [1,2] benzothiazol-4-ylmethanesulfonylmethyl, 3-CF 3 - [1,2] benzothiazol-4-ylmethanesulfonylmethyl, 6- CF 3 - [1,2] benzothiazol-7-ylmethanesulfonylmethyl, 6-CN- [1,2] benzothiazol-7-ylmethanesulfonylmethyl, 3 -CF 3 - [1,2] benzothiazol-7-ylmethanesulfonylmethyl, 5-F- [1,2] benzothiazol-3-ylmethanesulfonylmethyl , [2,3] benzothiazol-7-ylmethanesulfonylmethyl, 6-CF 3 - [2,3] benzothiazol-7-ylmethanesulfonylmethyl, 1-CF 3 - [2,3] benzothiazol-7-ylmethanesulfonylmethyl, 5'CF 3 - [2,3 ] benzothiazol-4-ylmethanesulfonylmethyl, 26,5-CN- [2,3] benzothiazol-4-ylmethanesulfonylmethyl [group, 1-CF3- [2,3] benzothiazol-4-ylmethanesulfonylmethyl, 4-CF3-2-CH3- thiazol-5-ylmethanesulfonylmethyl, 4-CF 3 -thiazol-5-ylmethanesulfonylmethyl, 4-CF 3 -2-phenyl-thiazol-5-ylmethanesulfonylmethyl, 5-CF 3 -2-CH 3 -thiazol-4-ylmethanesulfonyl [methyl, 5-CF 3 - 2-Phenyl-thiazol-4-ylmethanesulfonylmethyl, 5-CH3-thiazol-2-ylmethanesulfonylmethyl, 5-CF3-thiazol-2-one sulfonylmethyl, 5-phenyl-thiazol-2-ylmethanesulfonylmethyl, 4-CH3-thiazol-2-ylmethanesulfonylmethyl, 4-CF3-thiazol-2-ylmethanone] phenylmethyl, 4-phenylthiazol-2-ylmethanesulfonylmethyl, 5-CH3-2- (Pyridin-2-yl) - [1,233] triazol-4-ylmethanesulfonylmethyl, 5-CF3-2- (quinolin-2-yl) - [1,2,3] ßππζ-4-ylmethanesulfonylmethyl 5-CF3-2- ( 4-Methylsulfonylphenyl) - [1,2,3] triazol-4-ylmethanesulfonylmethyl, 4,5-dimethyl- [1,2,4] triazol-3-ylmethanesulfonylmethyl chloride, 5-CF3-4-CH3- [ 1.2.4] iriazol-3-ylmethylphenylmethyl, 4-CH3-5-phenyl- [1,2,4] triazol-3-ylsulfonylmethyl, 5-CF3-4-cyclopropyl- [112,4] triazole-3 -ylmethanesulfonylmethyl, 2,5-dimethyl- [1.2.4] triazol-3-ylmethanesulfonylmethyl-glucose, 5-CF3-2-CH3- [1,2,4] triazol-3-ylmethanesulfonylmethyl, 2- CFl3-5 -phenyl- [1,2,14] triazol-3-ylidene-sulfonylmethyl-2-cyclopropyl-5-phenyl- [1,2,4] -azol-3-ylmethanone-sulfonyl-ethyl, 5-CF3-1-CHS- [1 ^. lyriazol-5-ylmethanesulfonylmethyl, 1-CH3-5-phenyl- [1,2,4] triazol-3-yl thanesulfonylmethyl, 5-CH 3 -1-phenyl- [1.2.4] iriazol-3-ylmethanesulfonylmethyl, 3-CH 3 - [1,2,4] oxadiazole-5-methanesulfonylmethyl, 3-CF 3 - [1,2,4] ] oxadiazol-5-yl-ethanesulfonylmethyl-1-phenyl-1H-oxadiazol-5-ylmethanesulfonylmethyl, 5-CH3 [1,2,4] oxadiazol-3-ylmethanesulfonylmethyl, 5-CF3- [1,2,4] oxadiazole - 3-ylmethanesulfonylmethyl, 5-phenyl- [1,2,4] oxadiazole-3-methanesulfonylmethyl, 2-CH 3 - [1,3,4] oxadiazol-5-ylmethanesulfonylmethyl, 2-CF 3 - [1,3,4] oxadiazol-54-methanesulfonylmethyl-2-phenyl- [1,3,4] oxadiazol-5-yl-ethanesulfonylmethyl, 3-CH3- [1,2,4] iiadiazol-5-ylmethanesulfonylmethyl, S-CF1-Fluoro-thiazol-5-ylmethanesulfonylmethyl, 3- Phenyl- [1, 4-thiadiazol-5-ylmethanesulfonylmethyl] -S-CHa-fl, 2,4] thiadiazol-5-ylsulfonylmethyl, 5-CF3- [1,2,4] thiadiazol-3-methanesulfonylmethyl, 5-phenyl- [1,2,4] Thiadiazol-3-ylmethanesulfonylmethyl, 2-CH3- [1,3,4] iiadiazol-5-ylmethanesulfonylmethyl, 2-CF3- [1,3,4] thiadiazol-5-ylmethanesulfonate nylmethyl, 2-phenyl- [1,3,4] iiadiazol-5-ylmethanesulfonylmethyl, 2,2-difluoropyrrolidinylmethanesulfonylmethyl, 3,3-difluoropyrrolidinylmethanesulfonylmethyl, 3-CF3-N-CH3-pyrrol-2-ylmethanesulfonylmethyl-ring, 3-CN-N -CH3-pyrrol-2-ylmethanesulfonylmethyl, 4-CF3-N-CH3-pyrol-2-ylmethanesulfonylmethyl, 4- (1-CH3-1-hydroxyethyl) -N-CH3-pyrrol-2-ylmethanesulfonylmethyl, 1,3-dimethylpyrrole -2-ylmethanesulfonylmethyl, 4-CF3-N-CH3-pyrrol-3-ylmethanesulfonylmethylgmpa, 4-CN-N-CH3-pyrrol-3-ylmethanesulfonylmethyl, 4-CN-N- (3J3,3-trifluoropropyl) pyrrole-3 -ylmethanesulfonylmethyl-2-CF3-N-CH3-pyrrole-3-ylmethanesulfonylmethylamino, 2-CF3-N-phenyl-pyrrol-3-ylmethanesulfonylmethyl, 4-CF3-pyrrol-2-methanesulfonylmethyl, 4- (1-CH3-1-hydroxyhexyl) ) Pyrrol-2-ylmethanesulfonylmethyl, 27 27 LV 13669 3-CH3-pyrrol-2-ylmethanesulfonylmethyl, 4-CF3-pyrrol-3-ylmethanesulfonylmethyl, 2-CF3-pyrrole-2-ylmethanesulfonylmethyl, 3-CF3-pyrrole-2 - ilmethanesulfonylmeyl, 2-CF3-pyrrole-4-ylmethyl n-sulfonylmethylgmpa, 2-CF3-N-CH3-pyrrol-4-ylmethanesulfonylmethyl, 3-CF3-fur-2H-methanesulfonylmethyl, 3-CN-fur-2-ylmethanesulfonylmethyl, 3-CF3-fur-4-ylmethanesulfonylmethyl-ring, 3- CN-fur'4-ylmethanesulfonylmethyl, 2-CF3-fur-3-ylmethanesulfonylmethyl, 3'CF3-thiazol-2-ylmethanesulfonylmethyl, 3-CN-thiazol-2-ylmethanesulfonylmethyl; 3-CF 3 -thiazol-4-ylmethanesulfonylmethyl, 3-CN-thiazol-4-ylmethanesulfonylmethyl, 2-CF 3 -thiazol-3-methanesulfonylmethyl, N-CF 13 -3-CF 3 -1H-pyrazol-5-ylmethanesulfonylmethyl, N-CH 3 - 3- (1-CH3-1-Hydroxyethyl) -1H-pyrazol-5-ylmethanesulfonylmethyl, N-CH3-3-phenyl-1H-pyrazol-5-ylmethanesulfonylmethyl, N-CH3-3-CF3-1H-pyrazof- 4-ylmethanesulfonylmethyl, N-CH3-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl, N-phenyl-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl, N-phenyl-3-CF3-1 H -pyrazol-4-one 1-methanesulfonylmethyl, N-febii-5-CF3-1H-pyrazole-34lmethanesulfonylmethyl, (N-CF) 3-4-CF3-1H-imidazol-2-ylmethanesulfonylmethyl, [N-CH3-4- ( 1-CH3-1-Hydroxyethyl) -1H-imidazol-2-ylmethanesulfonylmethyl, (N-CH3-4-phenyl-1H-imidazol-2-ylmethane) sulfonylmethyl-1-N-CH3-3-CF3-1H-pyrazole- 4-Methanesulfonylmethylgmpa, (N-CH3-2-CF3-1H-imidazol-5-methanesulfonylmethyl (N-CH3-2-phenyl-1 H -imidazol-5-ylmethan) sulfonylmethyl, (N-CH3-5-CF3) 1 H -imidazol-4-ylmethan) sulfonyl ethyl (N-phenyl-5-CF3-1H-imidazol-5-ylmethan) sulfonylmethyl, 4-CN- [1,2] oxazol-5-methanesulfonylmethyl, 4-CN-3-phenyl [1,2] oxazole -5-methanesulfonylmethyl, 4-CN- [1,2] oxazol-3-ylmethanesulfonyl [methyl, 4-CN-5-phenyl- [1,2] oxazol-3-yl] -methanesulfonylmethyl-4-CN-isothiazol-5-yl 4-CN-isothiazol-5-ylmethanesulfonylmethyl, 4-CN-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl, 4-CF3- [1,2] oxazole, 4-CF3- [1,2] oxazole -5-ylmethanesulfonylmethyl, 4-CF 3 -3-CH 3 - [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CF 3 -3-phenyl- [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CF 3 - [1,2] oxazol-3-ylmethanesulfonyl-ethyl, 4-CF3-5-CH3- [1,2] oxazol-3-methanesulfonylmethyl, 4-CF3-5-phenyl- [1,2] oxazol-3-ylmethanesulfonylmethyl, 3 - CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl, 4-CF3- [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CF3-3- CFI3- [1,2] oxazol-5-ylmethanesulfonylmethyl a, 4-CF3-3-phenyl- [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CF3- [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CFa-S-CH5-fl] ilmethanesulfonylmethyl, 4-CF3-5-phenyl- [1,2] oxazol-3-ylmethanesulfonylmethyl, 3-CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl 4-CF 3 - [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CH 3 -3-phenyl- [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CH 3 - [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CH 5 -S-phenyl-1 H -hexazol-5-ylmethanesulfonylmethyl, 28 3 -CH 3 - [1- (4-hydroxymethyl) methyl] -5-CH 3 - [1,2] oxazol-4-ylmethanesulfonylmethyl, 4-CH 3 -isothiazol-5 -ylmethanesulfonylmethyl, 4-CH3-3-phenyl-isothiazo [-5-ylmethanesulfonylmethyl, 4-CH3-isothiazol-3-ylmethanesulfonyl-methyl] -amino, 4-CH3-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl, 3-CH3-isothiazol-4-yl 5-CH 3 -isothiazol-4-ylmethanesulfonylmethyl, 4-CF 3 -2-CH 3 - [1,3] oxazol-5-ylmethanesulfonylmethyl, 4-CF 3 - [1,3] oxazole ilmethanesulfonylmethyl, 4-CF3-phenyl- [1,3] oxazol-5-ylmethanesulfonylmethyl, 5-CF3-2-CH3- [1,3-oxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,3] oxazol-4-ylmethanesulfonylmethyl] , 5-CF3-2-Phenyl- [1,3] oxazol-4-ylmethanesulfonylmethyl, 5-CH3- [1,3] oxazol-2-ylmethanesulfonylmethyl, 5-CFs-fl.Soxazol-4-methanesulfonylmethyl, 5-phenyl- [1,3] oxazol-2-ylmethanesulfonylmethyl, 4-CH 3 - [1,3] oxazol-2-ylmethanesulfonylmethyl, 4-CF 3 - [1,3] oxazol-4-ylmethanesulfonylmethyl, 4-phenyl- [1,3] oxazole- 2-ylidenhanesulfonylmethyl, N-methylindol-2-ylmethanesulfonylmethyl, 3-CF3-indol-2-ylmethanesulfonylmethyl, 3-CF3-N-methylindol-2-ylmethanesulfonylmethyl, 5-fluoro-N-methylindol-2-ylmethanesulfonylmethyl , N-Methylindol-3-ylmethanesulfonylmethyl-J-ring, 2-CF3-indol-3-ylmethanesulfonylmethyl, 2-CF3-N-methylindol-3-ylmethanesulfonylmethyl, 5-fluoro-N-methylindol-3-ylmethanesulfonylmethyl, 5-CF3 -N-methylindol-4-ylmethanesulfonylmethyl, 5-CN-N-mstylindol-4-ylidene Phenylimidyl, 2-CF3-N-methylindol-4-ylmethanesulfonylmethyl, 3-CF3-N-methylindol-4-ylmethanesulfonylmeyl, 6-CF3-N-methylindol-7-ylmethanesulfonylmethyl, 6-CN-N- methylindol-7-ylmethanesulfonylmethyl, 2-CF3-N-methylindol-7-ylmethanesulfonylmethyl, 3-CF3-N-methylindoF7-methanesulfonylmethyl, benzofuran-2-ylmethanesulfonylmethyl, 3-CF3-benzofuran-2-ylmethanesulfonylmethyl, 3 - CN-benzofuran-2-ylmethanesulfonylmethyl, 5-F-benzofuran-2-methanesulfonylmethyl, benzofuran-3-methanesulfonylmethyl, 2-CF3-benzofuran-3-ylmethanesulfonylmethyl, 2-CH3-benzofuran-3-ylmethanesulfonylmethyl, 5-F- benzofuran-3-ylmethanesulfonylmethyl, 5-CF3-benzofuran-4-ylmethanesulfonylmethyl, 5-CN-benzofuran-4-ylmethanesulfonylmethyl, 2-CF3-benzofuran-4-ylmethanesulfonylmethyl, 3-CF3-benzofuran-4- ylmethanesulfonylmethyl, 6- CF 3 -benzofuran-7-ylmethanesulfonylmethyl, 6-CN-benzofuran-7-ylphenenesulfonylmethyl, 2-CF 3 -benzofuran-7-ylmethanesulfon phonylmethyl, 3-CF 3 -benzofuran-7-ylmethanesulfonylmethyl, benzothen-2-ylmethanesulfonylmeyl, (3 -CF 3-benzothen-2-ylmethane) suffonylmethyl, 29 29 LV 13669 (S-CN-benzothen-1-ylmethanesulfonylmethyl, (5-F) benzothen-2-ylmethane) sulfonylmethyl, benzothen-3-ylmethanesulfonylmethyl, (2-CF3-benzoten-3-ylmethane) sulfonylmethyl, (2-CH3-benzothen-3-ylmethane) sulfonylmethyl, (5-fluorobenzothen-3-ylmethan) sulfones methyl, (5-CF3-benzothen-4-ylmethane) suffonyl methyl, (5-CN-benzothen-4-ylmethane) sulfonylmethyl, (2-CF3-benzothen-4-ylamine) sulfonylmethyl, (3-CF3) benzothen-4-ylmethane) sulfonylmethyl, (6-CF3-benzophen-7-ylmethane) sulfonylmethyl, (6-CN-benzothen-7-ylmethane) su (phonylmethyl, (2-CF3-benzothen-7-ylmethane)) sulfonylmethyl, (3-CF3-benzothiol-74lmethane) sulfonylmethyl, N-methylbenzimidazol-2-ylmethylsulfonylmethyl, (5-fluoro-N-methyl [benzimidazol-2-ylmethanone [phenylmethyl, (N-methylindazol-3-ylmethane) sulfonylmethyl] , (5-Fluoro-N-methylindazol-3-ylmethane) sulfonylmethyl, (2-CF3-N-methylbenzimidazol-4-ylmethan) sulfonylmethyl, (2-CF3-N-methylbenzimidazol-7-ylmethan) sulfonylmethyl [ , (N-methylindazol-4-ylmethan) sulfon [methyl, (5-CF3-N-methylindazol-4-ylmethane) sulfonylmeyl, (3-CF3-N-methylindazol-4-ylmethane) sulfonylmethyl, (6- CF3- N-methylindazol-7-ylmethyl) with [methylmethyl, (6-CN-N-methylindazol-7-ylmethane) sulfonylmethyl or (3-CF3-N-methylindazol-7-ylmethane) sLi! meiyl.

[0112] Iepriekš minētajās grupās stereoķīmija pie oglekļa, ar kuru saistīta R5, ir (R), un ar kuru saistītas R4 un R6 ir (S).In the above-mentioned groups, the stereochemistry at the carbon to which R5 is attached is (R) and to which R4 and R6 are attached (S).

[0113] iepriekš minētajās grupās stereoķīmija pie oglekļa, ar kuru saistītas R° un R6, ir (R) un, ar kuru saistīta R4, ir (S).In the above-mentioned groups, the stereochemistry at the carbon to which R 0 and R 6 are attached is (R) and to which R 4 is (S).

[0114] (B) Cita savienojumu ar formulu (!) grupa, kurai dodama priekšroka, ir tā, kurā: R3 ir aikilgrupa, labāk metilgrupa vai etilgrupa un R4 ir alkilgrupa, labāk metilgrupa, etilgrupa, propiigrupa vai butiigrupa, un vēl labāk R4.ir metilgrupa. Labāk R3 un R4 ir metilgrupa.(B) A preferred group of other compounds of formula (I) is wherein: R 3 is alkyl, preferably methyl or ethyl, and R 4 is alkyl, preferably methyl, ethyl, propyl or buty, and more preferably R 4 .and methyl. Preferably R3 and R4 are methyl.

[0115] (C) Vēl viena savienojumu ar formulu (I) grupa, kurai dodama priekšroka, irtā, kur R3 un R4 kopā ar oglekja atomu, ar ko tās ir savienotas, veido cikfoalkilēnu, labāk ciklopropilēnu, ciklopentilēnu vai cikloheksilēnu, vēl labāk ciklopropilēnu.(C) Another preferred group of compounds of formula (I) wherein R3 and R4 together with the carbon atom to which they are attached form cycloalkylene, preferably cyclopropylene, cyclopentylene or cyclohexylene, more preferably cyclopropylene. .

[0116] (D)) Vē! viena savienojumu ar formulu (I) grupa, kurai dodama- priekšroka, ir tā, kur R3 un R4 kopā ar oglekļa atomu, ar ko tās ir savienotās, veido piperidin-4-ilgrupu, kas pie slāpekļa atoma aizvietota ar etilgrupu, 2,2,2-trifiuoretil- vai ciklopropiigrupu, tetrahidropirān-4-ilgrupu, tetrahidrotiopirān-4-ilgrupu vai '1,1 -dioksotetrahidrotiopīrā 30 [0117] (E) Vēl viena savienojumu ar formulu (!) grupa, kurai dodama priekšroka, irtā, kur Rs ir haloalkilgrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifiuoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, un R7 un R8 ir ūdeņradis. Λ [0118] (F) Vēl viena savienojumu ar formulu (I) grupa, kurai dodama priekšroka, irtā, kur R6 ir haloalkilgrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifiuoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, un R8 ir ūdeņradis.[0116] (D)) Oh! one group of compounds of formula (I) which is preferred is where R 3 and R 4 together with the carbon atom to which they are attached form a piperidin-4-yl group substituted at the nitrogen atom with an ethyl group of 2.2; , 2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyrene [0117] (E) A further preferred group of compounds of formula (!) Is where R 8 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, and R 7 and R 8 are hydrogen. (F) Another preferred group of compounds of formula (I) wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2 - pentafluoroethyl, and R8 is hydrogen.

[0119] (G) Vēl viena savienojumu ar formulu (I) grupa, kurai dodama priekšroka, irtā, kur R6 ir haloalkilgrupa, labāk difluormetilgrupa, trifluormetilgrupa, 2,2,2-trifiuoretilgrupa vai 1,1,2,2,2- pentafluoretilgrupa, R7 ir alkilgrupa, labāk metilgrupa, etilgrupa vai propilgrupa, un R8 ir ūdeņradis.(G) Another preferred group of compounds of formula (I) wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2- pentafluoroethyl, R7 is alkyl, preferably methyl, ethyl or propyl, and R8 is hydrogen.

[0120] (H) Vēl viena savienojumu ar formulu (I) grupa, kurai dodama priekšroka, irtā, kur R6 ir haloalkilgrupa, labāk 1,1,2,2,2-pentafluoretilgrupa vai 1,1,2,2,3,3,3-heptafluorpropiigrupa, R7 un R8 ir ūdeņradis.(H) Another preferred group of compounds of formula (I) wherein R6 is haloalkyl, preferably 1,1,2,2,2-pentafluoroethyl or 1,1,2,2,3, 3,3-Heptafluoropropyl, R7 and R8 are hydrogen.

[0121] Grupu (B)-(H), kurām dodama priekšroka, starpā, savienojumu grupas, kurām dodama priekšroka, irtās, kur R1, R2, R°, R6, R7 un R8 ir tādas, kas iepriekš definēts (A) grupai.Preferred groups of groups (B) - (H) to be preferred include those wherein R 1, R 2, R 0, R 6, R 7 and R 8 are as previously defined for (A) .

[0122] Grupu (D)-(H), kurām dodama priekšroka, starpā, savienojumu grupas, kurām dodama priekšroka, irtās, kur R1, R2, R3, R4 un R° ir tādas, kas iepriekš definēts (A) grupai.Preferred groups of groups (D) - (H) to be preferred include those wherein R 1, R 2, R 3, R 4 and R 0 are as previously defined for group (A).

[0123] Jāuzsvēr, ka atsauces uz· iepriekš minētajiem izgudrojuma realizācijas variantiem, kuriem dodama priekšroka, satur visus kombīnējumus no atsevišķām grupām un grupām, kurām dodama priekšroka, ja nav noteikts citādi.It should be emphasized that references to the above-mentioned embodiments of the invention for which preference is given include all combinations of individual groups and groups which are preferred unless otherwise specified.

[0124] Raksturīgākais savienojums no savienojumu ar formulu (I) skaita, kur R1 ir ūdeņradis, R6 irtrifluormetilgrupas un citas grupas saskaņā ar turpmāk mīnēto 1.tabulu, ir šādas:[0124] The most common compound of the formula (I) wherein R1 is hydrogen, R6 is trifluoromethyl and the other groups according to Table 1 below are as follows:

fa ga H Ķ5 0fa ga H5 0

yWJ 0 R3 R* ļ LV 13669yWJ 0 R3 R * ll 13669

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[0126] Izgudrojumā aprakstītos savienojumus var iegūt ar paņēmieniem, kas atspoguļoti turpmāk minētajās reakciju shēmās.[0126] The compounds described in the invention can be obtained by the techniques illustrated in the following reaction schemes.

[0127] Izejvielas un reaģentus, kas izmantojami šo savienojumu iegūšanai, var iegādāties no tādiem tirdzniecības piegādātājiem kā Aldrich Chemical Co., (Milvvaukee, Wis.), Bachem (Torrance, Calif.) vai Sigma (St. Louis, Mo.) vai pagatavot ar paņēmieniem, kas zināmi šīs jomas speciālistiem saskaņā ar procedūrām, kas aprakstītas šādā literatūrā: Fieserand Fieser's Reaģents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemisiry, (John Wiley and Sons, 4th Edition) un Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Šīs shēmas tikai ilustrē dažus paņēmienus, ar kuriem var sintezēt šajā izgudrojumā aprakstītos savienojumus, un iespējamas dažādās šo shēmu modifikācijas un tās var izmantot šīs nozares speciālisti, . kuri atsauksies uz šo izgudrojumu.Raw materials and reagents to be used to obtain these compounds may be purchased from commercial suppliers such as Aldrich Chemical Co., (Milvvaukee, Wis.), Bachem (Torrance, Calif.) Or Sigma (St. Louis, Mo.) or be prepared by techniques known to those skilled in the art according to the procedures described in Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemisiry (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes only illustrate some of the techniques that can be used to synthesize the compounds described in the present invention, and various modifications of these schemes are possible and can be used by those skilled in the art. who will refer to this invention.

[0128] Izejvielas un reakcijas starpproduktus, ja vēlas, var atdalīt un attīrīt ar tradicionālām metodēm, ieskaitot, bet ar minēto neierobežojoties, filtrāciju, destilāciju, kristalizāciju, hromatogrāfiju un tamlīdzīgi. Šos materiālus var raksturot ar tradicionālām metodēm, ieskaitot fizikālās konstantes un spektrālo informāciju.[0128] The raw materials and reaction intermediates, if desired, can be separated and purified by conventional methods including, but not limited to, filtration, distillation, crystallization, chromatography and the like. These materials can be characterized by traditional methods, including physical constants and spectral information.

Ja nav norādīts citādi, šeit aprakstītās reakcijas risinās atmosfēras spiedienā temperatūras diapazonā no aptuveni -78 °C līdz aptuveni 150°C, labāk no aptuveni 0°C līdz aptuveni 125°C un vēl labāk istabas (vai apkārtējā) temperatūrā, piemēram, aptuveni 20°C.Unless otherwise stated, the reactions described herein will be carried out at atmospheric pressure in a temperature range of about -78 ° C to about 150 ° C, preferably from about 0 ° C to about 125 ° C, and more preferably at room (or ambient) temperature, e.g. ° C.

[0129] Veicot turpmāk aprakstītās reakcijas, var rasties nepieciešamība pēc reaktīvo funkcionālo grupu aizsardzības, aizsargājot, piemēram, tādas grupas kā hidroksilgrupas, aminogrupas, iminogrupas, tiogrupas vai karboksilgrupas, ja nepieciešama attiecīgas grupas klātbūtne gala produktā, lai izslēgtu šo grupu nevēlamu piedalīšanos reakcijās. Tradicionālas aizsargājošās grupas var izmantot saskaņā ar standarta procedūrām, skat., piemēram, T.W.The reactions described below may require protection of reactive functional groups such as protecting groups such as hydroxyl groups, amino groups, imino groups, thiogroups, or carboxyl groups if the presence of a corresponding group in the final product is required to exclude the unwanted participation of these groups in the reactions. Traditional protecting groups can be used according to standard procedures, see, e.g., T.W.

Greene un P.G. M. Wuts in “Protective Groups īn Organic Chemistn/&quot; John Wiley and Sons, 1999.Greene and P.G. M. Wuts in “Protective Groups and Organic Chemistn / &quot; John Wiley and Sons, 1999.

[0130] Savienojumus ar formulu (I), kur R1, R2, R3, R4, R5, R6 un R8 ir kā definēts izgudrojuma kopsavilkumā un R7 ir ūdeņradis, var iegūt, rīkojoties kā aprakstīts turpmāk reakcijas 1.shēmā. 1.shēma 40 40 Re Rs Ο .1 1' f A AR ΗζΝ^Υ O 2 i-Vv^ Ra N γ ’a 0Compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are as defined in the Summary of the Invention and R 7 is hydrogen may be obtained by following the procedure described in Reaction Scheme 1 below. 1 scheme 40 40 Re Rs Ο .1 1 'f A AR ΗζΝ ^ Υ O 2 i-Vv ^ Ra N γ' a 0

Rs A /V^vV'^2 R‘ ti T X. i H 0 B? R1 o RĒ R5 Λν 4 ° R5 0 li 4&gt; [0131] Ja keions ar formulu 1, kur R6 un R8 ir kā definēts izgudrojuma kopsavilkumā, reaģē ar α-aminoesteri ar formulu 2, kur R ir karboksilgrupu aizsargājošā grupa, labāk alkilgrupa, labāk metilgrupa, un R5 ir kā definēts izgudrojuma kopsavilkumā, reducēšanas aminēšanas reakcijas apstākļos, tad iegūst savienojumu ar formulu 3. Reakciju veic tāda piemērota atūdeņotāja klātbūtnē, kā TiCI4, magnija sulfāts, izopropiltrifluoracetāts, tādas bāzes · klātbūtnē kā diizopropiletilamīns, piridīns un tamlīdzīgi, un tādā piemērotā organiskā šķīdinātājā, kā mefilēnhlorīds, iegūstot imīnu. Imīnu reducē ar tādu piemērotu reducējošo reaģentu kā nātrija borhidrīds, nātrija ciānoborhidrīds un tamlīdzīgi, tādā piemērotā organiskā šķīdinātājā kā metanols, etanols un tamlīdzīgi.Rs A / V? R1 o R5 5ν 4 ° R5 0 li 4 &gt; [0131] When the keion of formula 1 wherein R6 and R8 are as defined in the Summary of the Invention, reacts with an α-aminoester of formula 2, wherein R is a carboxyl protecting group, preferably an alkyl group, preferably a methyl group, and R5 is as defined in the Summary of the Invention. The reaction is carried out in the presence of a suitable dehydrator such as TiCl4, magnesium sulfate, isopropyl trifluoroacetate, in the presence of a base such as diisopropylethylamine, pyridine and the like, and in a suitable organic solvent such as mefylene chloride to give the imine. The imine is reduced with a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride and the like, in a suitable organic solvent such as methanol, ethanol and the like.

[0132] Tādi savienojumi ar formulu 1 kā 2,2,2-trifiuormetilacetfenons un 2,2,2,4 - tetrafluoraceffencns ir pieejami tirdzniecībā. Citus var iegūt ar paņēmieniem, kas labi zināmi šīs nozares speciālistiem, a- aminoesterus ar formulu 2 var iegūt ar paņēmieniem, kas labi zināmi šīs nozares speciālistiem, piemēram, PCT pieteikumu ar publikācijas Nr. WO 03075836, WO 00/55144, WO 01/19816, WO 02/20485, WO 03/029200, ASV izdalītais pieteikums Nr. 60/422,337, ASV patents Nr. 6,353,017B1, 6.492.662B1, 6,353,017 B1 un 6,525,036B1, 6,229,011B1, 6,610,700 - šie izgudrojumi šeit iekļauti ar atsauci visā to pilnībā.[0132] Compounds of formula 1 such as 2,2,2-trifluoromethylacetophenone and 2,2,2,4-tetrafluoraceffencns are commercially available. Others can be obtained by techniques well known to those skilled in the art, the α-aminoesters of formula 2 can be obtained by techniques well known to those skilled in the art, such as the PCT application with publication no. WO 03075836; WO 00/55144; WO 01/19816; WO 02/20485; WO 03/029200; 60 / 422,337, U.S. Pat. 6,353,017B1, 6,492,662B1, 6,353,017 B1 and 6,525,036B1, 6,229,011B1, 6,610,700 - these inventions are incorporated herein by reference in their entirety.

[0133] Estera grupas hidroiīzes savienojumā 3 rezultātā iegūst savienojumu ar formulu 4. Hidroiīzes apstākļi atkarīgi no aizsargājošās grupas tipa. Piemēram, ja R ir alkilgrupa, hidrolīzi veic ūdens bāziskās hidroiīzes apstākļos, iegūstot attiecīgo skābi ar formulu 4. Parasti reakciju veic ar cēzija karbonātu, litija hidroksīdu un tamlīdzīgi tāda alkohola ūdens šķīdumā, kā metanols, etanols un tamlīdzīgi.[0133] The hydrolysis compound 3 of the ester group results in a compound of formula 4. The hydrolysis conditions depend on the type of protecting group. For example, when R is alkyl, hydrolysis is carried out under aqueous basic hydrolysis to give the corresponding acid of formula 4. Generally, the reaction is carried out with cesium carbonate, lithium hydroxide and the like in an aqueous solution of alcohol such as methanol, ethanol and the like.

[0134] Pēc tam savienojums 4 reaģē ar α-hidroksiketoamīdu ar formulu 5, veidojot savienojumu ar formulu 6. Parasti reakciju veic tāda piemērota pievienojošā līdzekļa klātbūtnē kā, piemēram, benzotriazol-1-iloksitrispirolidīnfosfonija heksafluorfosfāts (PyBOP®), O-benzotriazol-1-il-Ν,Ν,Ν’, /V-tetrametil-uronija heksafluorfosfāts (HBTU), 0-(7-azabenzotriazol-1-il)-1,1,3,3-tetrametiluronija heksafluorfosfāts (HATU), 1-(3-dimetilaminopropil)-3-etilkarbodiimīda hidrohlorīds (EDO) vai 1,3-dicikloheksilkarbodiimīds (DCC), neobligāti 1-hidroksibenzotriazola (HOBT) klātbūtnē un tādas bāzes kā Λ/,/V-diizopropiletilamīns, trietilamīns, N-metilmorfolīns un tamlīdzīgi klārbūtnē. Parasti reakciju veic temperatūrā no 20°C līdz 30°C, labāk ap 25°C un reakcijas pabeigšana aizņem no 2 līdz 24 stundām. Reakcijai piemēroti šķīdinātāji ir inerti organiski šķīdinātāji, tādi kā 41 LV 13669 halogenizētie organiskie šķīdinātāji (piemēram, metilēna hlorīds, hloroforms un tamlīdzīgi), acetonitrils, /^/V-dimetilformamīds, tādi pie ēteru grupas piederoši šķīdinātāji, kā tetrahidrofurāns, dioksāns un tamlīdzīgi.[0134] The compound 4 then reacts with α-hydroxycetoamide of formula 5 to form a compound of Formula 6. Generally, the reaction is carried out in the presence of a suitable additive such as, for example, benzotriazol-1-yloxyrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), O-benzotriazole-1. -yl-Ν, Ν, Ν ', N-tetramethyluronium hexafluorophosphate (HBTU), O- (7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluron hexafluorophosphate (HATU), 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDO) or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of 1-hydroxybenzotriazole (HOBT) and bases such as, / N-diisopropylethylamine, triethylamine, N-methylmorpholine and the like . Generally, the reaction is carried out at a temperature between 20 ° C and 30 ° C, preferably about 25 ° C, and the completion of the reaction takes from 2 to 24 hours. Suitable solvents for the reaction include inert organic solvents such as halogenated organic solvents (e.g. methylene chloride, chloroform and the like), acetonitrile, N-dimethylformamide, solvents belonging to the ether group such as tetrahydrofuran, dioxane and the like.

[0135] Alternatīvi iepriekš minēto svienošanas posmu var veikt, savienojumu 4 vispirms pārvēršot tādā aktīvā skābes atvasinājumā, kā sukcīnimīda esteris, un pēc tam šo esteri pakļaujot reakcijai ar α-hidroksiketoamīdu ar formulu 5. Reakcijas pabeigšana parasti aizņem no 2 līdz 3 stundām. Šīs reakcijas apstākļi atkarīgi no aktīvā skābes atvasinājuma veida. Piemēram, ja šis atvasinājums ir savienojuma 4 skābais hlorīds, tad reakciju veic piemērotas bāzes klātbūtnē (piemēram, izmantojot trietilamīnu, diizopropiletiiamīnu, piridīnu un tamlīdzīgi). Reakcijai piemēroti šķīdinātāji ir polārie organiskie šķīdinātāji tādi, kā acetonitrils, A/,A/-dimetilformamīds, dihlormetāns vai jebkādi piemēroti šo šķīdinātāju maisījumi. Savienojumus ar formulu 5 var pagatavot ar paņēmieniem, kas labi zināmi šīsnozares speciālistiem, piemēram, šos savienojumus var iegūt ar procedūrām, kas aprakstītas PCT pieteikumā Nr. WO 02/18369, kura rezultāti šeit iekļauti ar atsauci visā to pilnībā.Alternatively, the above-mentioned flux step can be carried out by first converting the compound 4 into an active acid derivative such as succinimide ester, and then reacting this ester with α-hydroxycetoamide of Formula 5. The completion of the reaction usually takes from 2 to 3 hours. The conditions of this reaction depend on the type of active acid derivative. For example, if this derivative is the acid chloride of compound 4, then the reaction is carried out in the presence of a suitable base (e.g., using triethylamine, diisopropylethylamine, pyridine and the like). Suitable solvents for the reaction are polar organic solvents such as acetonitrile, N, N-dimethylformamide, dichloromethane or any suitable mixture of these solvents. Compounds of formula 5 can be prepared by methods well known to those skilled in the art, for example, these compounds can be obtained by the procedures described in PCT application no. WO 02/18369, the results of which are incorporated herein by reference in their entirety.

[0136] Oksidējot hidroksilgrupu savienojumā 6 ar piemērotu oksidēšanas līdzekli, tādu kā ΟΧΟΝΕ®, iegūst savienojumu ar formulu (I).[0136] Oxidation of the hydroxyl group in compound 6 with a suitable oxidizing agent such as ΟΧΟΝΕ® yields a compound of formula (I).

[0137] Alternatīvi savienojumus ar formulu (I), kur R1, R2, R3, R4, R5, R6 un R8 ir kā definēts izgudrojuma kopsavilkumā, un R7 ir ūdeņradis, var iegūt, rīkojoties saskaņā ar turpmāk minēto reakcijas 2. shēmu. 2.shēma I £ % %-J* 1 Re ψ Jv „A &gt; R? ^ ? 8 S 16 R5 ψ rjB ļļŠ _ x A ,oh f? N ļf “* W h o .Gpe nAlternatively, compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are as defined in the Summary of the Invention and R 7 is hydrogen may be obtained by following the reaction scheme 2 below. Scheme 2 I £%% -J * 1 Re ψ Jv 'A &gt; R? ^? 8 S 16 R5 B rjB let _ x A, oh f? N w "* W h o .Gpe n

Savienojumam ar formulu 8, kur R5 ir kā definēts izgudrojuma kopsavilkumā un PG ir piemērota skābekļa aizsargājošā grupa, reaģējot ar hemiacetālu ar formulu 7, kur R6 ir ķā definēts izgudrojuma kopsavilkumā, iegūsi imīna savienojumu ar formulu 9. Savienojumu 9 apstrādājot ar litija organisko savienojumu ar formulu R8Li, kur R8 nav ūdeņradis, iegūst1savienojumu 10. Pēc tam likvidē skābekļa aizsargājošo grupu, oksidē iegūto alkoholu 11, kā rezultātā iegūst savienojumu ar formulu 4, kuru pēc tam pārvērš savienojumā ar formulu (I) kā minēts iepriekš 1.shēmas aprakstā. Piemērotās skābekļa aizsargājošās grupas un reakcijas apstākļi, kuros šīs grupas var pievienot un izņemt, aprakstīti Greene, T. W.; and Wuts, P. G. M.; Protecting Grou^s in Organic Synthesis; John Wiley &amp; Sons, Inc. 1999. 42For a compound of formula 8 wherein R5 is as defined in the Summary of the Invention and PG is a suitable oxygen protecting group reacting with the hemiacetal of Formula 7, wherein R6 is as defined in the Summary of the Invention, an imine compound of Formula 9 is obtained by treating Compound 9 with a lithium organic compound with Formula R8Li, wherein R8 is not hydrogen, yields a compound of 10. Then removing the oxygen protecting group, oxidizing the resulting alcohol 11, results in a compound of formula 4 which is then converted to a compound of formula (I) as described in Scheme 1 above. Suitable oxygen protecting groups and reaction conditions in which these groups can be attached and removed are described by Greene, T. W .; and Wuts, P. G. M .; Protecting Grou ^ s in Organic Synthesis; John Wiley &amp; Sons, Inc. 1999 42

Alternatīvi savienojumus ar formulu (I), kur R1, R2, R3, R4, R5, R6 un R7 ir kā definēts izgudrojuma kopsavilkumā un R8 ir ūdeņradis, var iegūt, rīkojoties saskaņā ar turpmāk minēto 3.reakcijas shēmu. 3.shēma 0 0 Vf1 HO' ΛAlternatively, compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined in the Summary of the Invention and R 8 is hydrogen may be obtained by following the reaction scheme 3 below. Scheme 3 0 0 Vf1 HO 'Λ

,OR, OR

Rc RĒ BFs,%0 R*Rc RE BFs,% 0 R *

.0R.0R

O Ϊ2 m [0138] Aminoskābes savienojumam ar formulu 2, kur R ir alkilgrupa un R5 ir kā definēts izgudrojuma kopsavilkumā, reaģējot ar hemiacetāla savienojumu ar formulu 7, iegūst savienojumu 2-(1-hidroksi-2,2,2-Īrifluoretilamino)acetātu ar formulu 12. Reakciju veic tādas skābes katalītiska daudzuma klātbūtnē, kā p-toluo!sulfoskābe, un tādā aromātiskā ogļūdeņraža šķīdinātājā, kā toluols, benzols un tamlīdzīgi.O Ϊ2 m For the amino acid compound of formula 2 wherein R is alkyl and R 5 is as defined in the Summary of the Invention by reacting with a hemiacetal compound of formula 7, compound 2- (1-hydroxy-2,2,2-trifluoroethylamino) acetate is obtained. The reaction is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, and in an aromatic hydrocarbon solvent such as toluene, benzene and the like.

[0139] Savienojumu 12 apstrādājot ar savienojumu ar formulu R6H, kur R7 ir arilgrupa vai heieroariigrupa, Frīdeļa-Kraftsa reakcijas apstākļos, vai trialkilalumīnija toluolā, iegūst savienojumu ar formulu 3, kuru pēc tam pārvērš savienojumā ar formulu (I) kā aprakstīts iepriekš.Treatment of compound 12 with a compound of formula R6H wherein R7 is aryl or a heteroaryl group under the conditions of the Friedel-Crafts reaction or trialkylaluminium in toluene affords the compound of formula 3 which is then converted to the compound of formula (I) as described above.

[0140] Alternatīvi savienojumu ar formulu (I), kur R1, R2, R3, R4, R5, R6 un R7 ir kā definēts izgudrojuma kopsavilkumā, un R8 ir ūdeņradis, var iegūt, rīkojoties saskaņā ar turpmāk aprakstīto reakcijas 4.shēmu. 4.shēma Fē Rz 1 RĒ ?5 *?·* R^OTf 13 + t X sOR‘ 0 14 1 1 neobīigši] t 1 - AV' - 15 15Alternatively, compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined in the Summary of the Invention and R 8 is hydrogen can be obtained by following the reaction scheme 4 described below. 4th Scheme Fz Rz 1? 5 *? · * R ^ OTf 13 + t X sOR '0 14 1 1 neobiggers] t 1 - AV' - 15 15

,OH R6' R? - «#Vtx ’ 5 17 sktiv&amp;is skābes 4tvaslnJ]ums vai līdz prekursoram (I) 1 2 [0141] Savienojumam ar formulu 13, kur R6 un R7 ir kā definēts izgudrojuma 3 kopsavilkumā, reaģējot ar savienojumu ar formulu 14, kur R’ ir ūdeņradis vai 4 karboksilgrupas aizsargājošā grupa un Rz ir R5 vai prekursora grupa 5 (piemēram, alkilēn-S-tritīigrupa, -alkilēn-S-alkilēnheteroarilgrupa un tamlīdzīgi) 6 līdz R5 grupai, iegūst savienojumu ar formulu 15. Reakciju veic piemērotā 7 tetrahidrofurānu, acetonitrilu, benzolu, toluolu, ksilēnu un tamlīdzīgi, vai šo šķīdinātāju maisījumos, un neobligāti organiskas vai neorganiskas bāzes klātbūtnē. Labāk, ja organiskā bāze ir trietilamīns, piridīns, N-metilmorfolīns, 8 organiskā šķīdinātājā, ieskaitot, bet ar minēto neierobežojoties, dietilēteri, 43 43 LV 13669 colidīns, diizopropīletilamīns un tamlīdzīgi. Labāk, ja neorganiskā bāze ir cēzija karbonāts, nātrija karbonāts, nātrija bikarbonāts un tamlīdzīgi. Neobligāti reakciju veic tāda žāvējošā līdzekļa klātbūtnē kā molekulārie sieti. Labāk, ja reakciju veic istabas temperatūrā., OH R6 'R? - "#Vtx" 5 17 sktiv &amp; is acid 4tvaslnJ] or precursor (I) 1 2 [0141] For a compound of formula 13, wherein R6 and R7 are as defined in the Summary of Invention 3, with a compound of formula 14 wherein R 'is hydrogen or a 4-carboxyl protecting group and Rz is R5 or a precursor group 5 (e.g., alkylene-S-trityl, -alkylene-S-alkylene-heteroaryl and the like) from 6 to R5 yields the compound of formula 15. The reaction is carried out with a suitable 7-tetrahydrofuran. , acetonitrile, benzene, toluene, xylene and the like, or mixtures of these solvents, and optionally in the presence of an organic or inorganic base. Preferably, the organic base is triethylamine, pyridine, N-methylmorpholine, 8 in an organic solvent including, but not limited to, diethyl ether, 43 43 LV 13669 colidine, diisopropylethylamine and the like. Better if the inorganic base is cesium carbonate, sodium carbonate, sodium bicarbonate and the like. Optionally, the reaction is carried out in the presence of a desiccant as a molecular sieve. The reaction is preferably carried out at room temperature.

[0142] Savienojumus ar formulu 13 var iegūt ar paņēmieniem, kas labi zināmi šīs jomas speciālistiem. Piemēram, savienojumu ar formulu 13, kur R ir fenilgrupa vai 4-fluorfenilgrupa un R irtrifluormetilgrupa, var viegli iegūt no tirdzniecībā pieejamā 2,2,2-trifluoracetofenona vai 2,2,2,4'-tetrafluoracetofenona, respektīvi, ketogrupu reducējot līdz alkohola grupai, izmantojot piemērotu reducējošo līdzekli, tādu kā nātrija borhidrīds, litija aluminīja hidrīds un tamlīdzīgi. Izmantojamais šķīdinātājs atkarīgs no reducējošā līdzekļa veida. Piemēram, ja izmanto nātrija borhidrīdu, reakciju veic tāda organiskā alkoholiskā šķīdinātāja klātbūtnē kā metanols, etanols un tamlīdzīgi. Ja izmanto litija alumīnija hidrīdu, reakciju veic tādā ēteriskā šķīdinātājā, kā tetrahidrofurāns un tamlīdzīgi. 2,2,2-trifluor-1 -fenifetanolam vai 2,2,2-trifluor-1-(4-fluorfeni!)etanolam reaģējot ar triflikanhidrīdu vai trifluormetānsulfonila hlorīdu, iegūst vēlamo savienojumu. Savienojumus ar formulu 13, kur R7 un R8 ir ūdeņradis un R6 ir 1,1,2,2,2-pentafluoretilgrupa, var iegūt no tirdzniecībā pieejamā 2,2,3,3,3-pentafluorpropēn-1-ola kā aprakstīts iepriekš. Optiski bagātināto savienojumu ar formulu 15 var iegūt, attiecīgo halogenizēto acetofenonu reducējot ar piemērotu reducējošo līdzekli, tādu kā kateholborāns vai BH3-DMS komplekss piemērota katalizatora klātbūtnē, tāda kā (S) vai (R)-oksazaborolidīns vai (S) vai (/?)-a,a-difenil-2-pirolidīnmetanols BBN klātbūtnē, iegūstot hirāiu alkoholu, ko pēc tam pārvērš savienojumā 13 kā aprakstīts iepriekš. Savienojumi ar formulu 14 pieejami tirdzniecībā vai arī tos var iegūt ar paņēmieniem, kas labi pazīstai šīs jomas speciālistiem.[0142] Compounds of formula 13 can be obtained by methods well known to those skilled in the art. For example, a compound of formula 13 wherein R is phenyl or 4-fluorophenyl and R is trifluoromethyl may readily be obtained from commercially available 2,2,2-trifluoroacetophenone or 2,2,2,4'-tetrafluoroacetophenone, i.e. by reduction of the ketogroup to alcohol. using a suitable reducing agent such as sodium borohydride, lithium aluminum hydride and the like. The solvent used depends on the type of reducing agent. For example, if sodium borohydride is used, the reaction is carried out in the presence of an organic alcoholic solvent such as methanol, ethanol and the like. When lithium aluminum hydride is used, the reaction is carried out in an ethereal solvent such as tetrahydrofuran and the like. 2,2,2-Trifluoro-1-phenyl-ethanol or 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol is reacted with triflic anhydride or trifluoromethanesulfonyl chloride to give the desired compound. Compounds of formula 13 wherein R7 and R8 are hydrogen and R6 is 1,1,2,2,2-pentafluoroethyl can be obtained from commercially available 2,2,3,3,3-pentafluoropropene-1-ol as described above. The optically enriched compounds of formula 15 can be obtained by reduction of the corresponding halogenated acetophenone with a suitable reducing agent such as catecholborane or BH3-DMS complex in the presence of a suitable catalyst such as (S) or (R) -oxazaborolidine or (S) or (/?). -a, α-diphenyl-2-pyrrolidinemethanol in the presence of BBN to give the hiral alcohol which is then converted into compound 13 as described above. Compounds of formula 14 are commercially available or can be obtained by techniques well known to those skilled in the art.

[0143] Karboksilgrupas aizsargājošo grupu izņemot no savienojuma ar formulu 15, kur R’ ir aizsargājošā grupa, iegūst savienojumu ar formulu 16. Apstākļi, kuros izņem karboksilgrupas aizsargājošo grupu, atkarīgi no karboksilgrupas aizsargājošās grupas tipa. Piemēram, ja R’ ir alkilgrupa, to izņem bāziskas hidrolizēs apstākļos, izmantojot tādas bāzes ūdens šķīdumu, kā litija hidroksīds, nātrija hidroksīds un tamlīdzīgi, un tādā alkoholiskajā šķīdinātājā, kā metanols, etanols un tamlīdzīgi. Bez tam, ja Rz grupa savienojumā 14 ir prekursora grupa R5 grupai, to var pārvērst R5 grupā pirms estera hidrolizēs posma vai pēc tam.[0143] The carboxyl protecting group, except from the compound of formula 15, wherein R 'is a protecting group, yields a compound of formula 16. The conditions for removal of the carboxyl protecting group depend on the carboxyl protecting group type. For example, if R 'is alkyl, it is removed under basic hydrolysis using a base aqueous solution such as lithium hydroxide, sodium hydroxide and the like, and in an alcoholic solvent such as methanol, ethanol and the like. In addition, if the Rz group in compound 14 is a precursor group for R5, it can be converted to R5 before the ester is hydrolyzed to the stage or thereafter.

[0144] Savienojumu 15 (kur R’ ir ūdeņradis) vai savienojumu16 pēc tam pārvērš aktivētajā skābes atvasinājumā 17 (X ir atšķeļamā grupa), kuram reaģējot ar aminoacetonitrīla savienojumu ar formulu 5, iegūst savienojumu ar formulu (I), ja Rz ir R5 vai prekursora savienojums savienojumam (!), ja Rz ir prekursora grupa R5. Aktivēto skābes atvasinājumu var pagatavot un pēc tam pakļaut reakcijai ar savienojumu 5 pakāpeniskā veidā vai arī aktivēto skābes atvasinājumu var pagatavot in situ savienojuma 5 klātbūtnē. Piemēram, ja aktivētais skābes atvasinājums ir skābes haiīds, tad to pagatavo, savienojumu 16 pakļaujot reakcijai ar tādu haiogenizējošu savienojumu, kā tionilhlorīds, oksalilhlorīds un tamlīdzīgi, un pēc tam pakļaujot reakcijai ar savienojumu 5. Alternatīvi aktivēto skābes atvasinājumu iegūst //7 situ, savienojumam16 un 5 44 reaģējot tāda piemērota pievienošanas līdzekļa klātbūtnē, kā, piemēram, benzotriazoM-iloksitrispirolidīnfosfonija heksafluorfosfāts (PyBOP®), 0-benzotriazol-1 -ιΊ-Λ/,Α/,Λ/'Λ/-tetrametiluronija heksafluorfosfatrs (HBTU), 0-(7-azabenzotriazol-1-il)-1,1,3,3-tetrametiluronija heksafluorfosfāts (HATU), 1-(3-dimetilamīnopropil)-3-etilkarbodiimīda hidrohlorīds (EDC), 1,3-dicikloheksilkarbodiimīds (DCC) un tamlīdzīgi, neobligāti 1-hidroksibenzotriazola (HOBT) klātbūtnē un tādas bāzes klātbūtnē kā N,N-diizopropiletilamīns, trietilamīns, A/-metilmorfolīns un tamlīdzīgi. Piemēroti organiskie šķīdinātāji ir inertie organiskie šķīdinātāji, tādi kā halogenizētie organiskie šķīdinātāji (piemēram, metilēna hlorīds, hloroforms un tamlīdzīgi), acefonitrils, N-dimetilformamīds, ēteriskie šķīdinātāji, tādi kā tetrahidrofurāns, dioksāns un tamlīdzīgi. Ja Rz ir prekursora grupa R5, to pārvērš R5 grupā, iegūstot savienojumu ar formulu (I), piemēram, -alkilēn-S-alkilēnheteroaril-grupu pārvēršot -a[kilēn-S02-alkilēnheteroarilgrupā oksidēšanas reakcijas apstākļos.The compound 15 (where R 'is hydrogen) or the compound 16 is then converted to the activated acid derivative 17 (X is a cleavable group), which reacts with the aminoacetonitrile compound of formula 5 to give a compound of formula (I) when R 2 is R 5 or \ t precursor compound for compound (!) when Rz is a precursor group R5. The activated acid derivative can be prepared and then reacted with the compound 5 in a stepwise manner, or the activated acid derivative can be prepared in situ in the presence of compound 5. For example, if the activated acid derivative is an acid halide, then it is prepared by reacting the compound 16 with a halogenating compound such as thionyl chloride, oxalyl chloride and the like, and then reacting with the compound 5. Alternatively, the activated acid derivative is obtained from // 7, for the bond 16 and 5 44 in the presence of a suitable additive such as, for example, benzotriazM-iloxytispyrrolidinphosphonium hexafluorophosphate (PyBOP®), 0-benzotriazol-1-ene-β, Α / Λ / ram -tetramethyluronium hexafluorophosphate (HBTU), 0 - (7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and like, in the presence of 1-hydroxybenzotriazole (HOBT) and in the presence of a base such as N, N-diisopropylethylamine, triethylamine, N-methylmorpholine and the like. Suitable organic solvents include inorganic organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform and the like), acetonitrile, N-dimethylformamide, essential solvents such as tetrahydrofuran, dioxane and the like. When R 2 is a precursor group R 5, it is converted to R 5 to give a compound of formula (I), for example, by converting an -alkylene-S-alkylene-heteroaryl group into -α [alkylene-SO 2 -alkylene-heteroaryl under oxidation reaction conditions.

[0145] Savienojumu ar formulu (I) var pārvērst citos savienojumos ar formulu (I). Piemēram: [0146] Savienojumu ar formulu (I), kas satur hidroksilgrupu, var pagatavot, izņemot alkilgrupu/benzilgrupu no alkoksi/benziloksi aizvietotāja; ja klāt ir skābes grupa, veic estera grupas hidrolīzi; ja klāt ir ciāngrupa, tad broma atomu izņem no attiecīgajiem savienojumiem ar formulu (I). Savienojumu ar formulu (I), kurš satur ciāngrupu, var pārvērst attiecīgajā karboksilgrupu saturošajā savienojumā, hidrolizējot ciāngrupu. Savukārt, karboksilgrupu var pārvērst estera grupā.[0145] The compound of formula (I) can be converted into other compounds of formula (I). For example: A compound of formula (I) containing a hydroxyl group may be prepared except an alkyl / benzyl group of an alkoxy / benzyloxy substituent; if an acid group is present, hydrolysis of the ester group is performed; if cyano is present, the bromine atom is removed from the corresponding compounds of formula (I). The compound of formula (I) containing a cyano group can be converted into the corresponding carboxyl-containing compound by hydrolysis of the cyano group. Conversely, the carboxyl group can be converted into an ester group.

[0147] Savienojumu ar formulu (I) kā farmaceitiski pieņemamu skābes adiiīvo sāli var iegūt, brīvajai savienojuma formai reaģējot ar farmaceitiski pieņemamu neorganisku vai'organisku skābi. Kā alternatīva, farmaceitiski pieņemamu bāzisku aditīvu savienojuma ar formulu (I) sāli var iegūt, brīvajai skābajai savienojuma formai reaģējot ar farmaceitiski pieņemamu neorganisku vai organisku bāzi. Neorganiskās un organiskās skābes un bāzes, kas piemērotas farmaceitiski pieņemamu savienojuma ar formulu (I) sāļu pagatavošanai, minētas šī pieteikuma dfinīciju nodaļā. Alternatīvi savienojuma ar formulu (I) sāju formas var pagatavot, izmantojot izejvielu var starpproduktu sājus.A compound of formula (I) can be obtained as a pharmaceutically acceptable acid addition salt by reacting the free form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable salt of a basic additive of formula (I) can be obtained by reacting the free acid form with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compound of formula (I) are mentioned in the Dinection section of this application. Alternatively, the mold forms of the compound of formula (I) may be prepared using raw materials as intermediate salts.

[0148] Savienojumu ar formulu (I) brīvās skābās vai bāziskās formas var pagatavot no attiecīgas bāzes aditīvā sāls vai skābes aditīvā sāls formas. Piemēram, savienojuma ar formulu (I) skābes aditīvo sāls formu var pārvērst attiecīgajā brīvajā bāziskajā formā, apstrādājot ar piemērotu bāzi (piemēram, amonija hidroksīda šķīdumu, nātrija hidroksīdu un tamlīdzīgi). Savienojuma ar formulu (I) bāzes aditīvo sāls formu var pārvērst attiecīgajā brīvajā skābes formā, apstrādājot ar piemērotu skābi (piemēram, sālsskābi utt.).[0148] The free acidic or basic forms of the compounds of formula (I) can be prepared from the corresponding base additive salt or acid addition salt form. For example, the acid addition salt of the compound of formula (I) may be converted to the corresponding free basic form by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide and the like). The additive salt form of the compound of formula (I) may be converted into the corresponding free acid form by treatment with a suitable acid (e.g. hydrochloric acid, etc.).

[0149] Savienojumu ar formulu (I) /V-oksīdus var iegūt ar paņēmieniem, kas zināmi šīs jomas speciālistiem ar parastu kvalifikācijas līmeni. Piemēram, N-oksīdus var iegūt, savienojuma ar formulu (I) neoksidētu formu apstrādājot ar oksidējošo savienojumu (piemēram, trifluorperetiķskābi, permaleīnskābi, 45 45 LV 13669 perbenzolskābi, peretiķskābi, mefa-hlorpe.roksibenzolskābi un tamlīdzīgi) piemērotā inertā organiskā šķīdinātājā (piemēram, halogenizētā ogļūdeņradī’ tādā kā dihlormetāns) aptuveni 0°C. Alternatīvi savienojumu ar formulu (!) N-oksīdus var pagatavot no piemērotas izejvielas /V-oksīda.[0149] The compound of formula (I) / V-oxides can be obtained by techniques known to those of ordinary skill in the art. For example, N-oxides can be obtained by treating a non-oxidised form of the compound of formula (I) with an oxidizing compound (e.g., trifluoroacetic acid, permaleic acid, 45 45 LV 13669 perbenzolic acid, peracetic acid, mepha-chloro-hydroxybenzoic acid and the like) in a suitable inert organic solvent (e.g. halogenated hydrocarbon such as dichloromethane at about 0 ° C. Alternatively, the N-oxides of the compound of formula (I) may be prepared from a suitable source of N-oxide.

[0150] Savienojumu ar formulu (I) neoksidēto formu var iegūt no savienojumu ar formulu (I) /V-oksīdiem, apstrādājot ar reducējošo līdzekli (piemēram, sēru, sēra dioksīdu, trifenilfosfīnu, litija borhidrīdu, nātrija borhidrīdu, fosfora trihlorīdu un tamlīdzīgi) piemērotā inertā organiskā šķīdinātājā (piemēram, acetonitrilā, etanolā, dioksāna ūdens maisījumā un tamlīdzīgi) temperatūrā .no 0°C līdz 80°C.The non-oxidized form of the compounds of formula (I) can be obtained from a compound of formula (I) / V-oxides by treatment with a reducing agent (e.g. sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and the like) at a suitable inert organic solvent (e.g., acetonitrile, ethanol, dioxane water, and the like) at. 0 ° C to 80 ° C.

[0151] Savienojumu ar formulu (!) prozāju atvasinājumus var iegūt ar paņēmieniem, kas zināmi šīs jomas speciālistiem ar parastu kvalifikācijas līmeni (piemēram, sīkāk skat. Saulnier et al. (1994), Bioorganic and Medicīnai Chemistry Letters, Voi. 4, p. 1985). Piemēram, piemērotas prozāles var pagatavot, neatvasinātu savienojumu ar formulu (I) pakļaujot reakcijai ar piemērotu karbamilēšanas līdzekli (piemēram, 1,1-aciloksialkilkarbonhloridātu, para-nitrofenilkarbonātu un tamlīdzīgi).[0151] Prodrug derivatives of formula (!) Can be obtained by techniques known to those of ordinary skill in the art (e.g., Saulnier et al. (1994), Bioorganic and Medical Chemistry Letters, Vol. 4, p. 1985). For example, suitable blanks can be prepared by subjecting the non-derived compound of formula (I) to a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonyl chloride, para-nitrophenylcarbonate and the like).

[0152] Aizsargātos savienojumu ar formulu (I) atvasinājumus var iegūt ar paņēmieniem, kas zināmi šīs jomas speciālistiem ar parastu kvalifikācijas līmeni. Detalizēts paņēmienu pārskats par aizsargājošo grupu pagatavošanu un izņemšanu minēts T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999.[0152] The protected compounds of formula (I) can be obtained by techniques known to those of ordinary skill in the art. A detailed overview of techniques for preparing and removing protective groups is provided by T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999

[0153] Šajā izgudrojumā aprakstītos savienojumus var ērti pagatavot vai izveidot izgudrojuma paņēmienu rezultātā kā solvātus (piemēram, hidrātus). Šajā izgudrojumā aprakstīto savienojumu hidrātus var ērti pagatavot, veicot rekristatizāciju no ūdens/orgāniskā šķīdinātāja maisījuma, izmantojot tādus organiskos šķīdinātājus, kā dioksīns, tetrahidrofurāns vai metanols.[0153] The compounds described in this invention can conveniently be prepared or produced as solvates (e.g., hydrates) as a result of the invention. The hydrates of the compounds described in this invention can be conveniently prepared by recrystallization from a water / organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0154] Savienojumus ar formulu (I) var pagatavot kā šo savienojumu individuālos stereoizomērus, šo savienojumu racēmisko maisījumu pakļaujot reakcijai ar optiski aktīvu atdalošu aģentu, veidojot diastereoizomēru pāri, atdalot no diastereomēriem un reducējot optiski tīru enantiomēru. Kaut arī enantiomēru atdalīšanu var veikt, izmantojot savienojumu ar formulu (I) kovalentos diastereoizomēru atvasinājumus, priekšroka dodama disociējamiem kompleksiem (piemēram, kristāliskiem diastereoizomēru sāļiem). Diastereoizomēriem ir izteiktas fizikālās īpašības (piemēram, kušanas temperatūra, vārīšanās temperatūra, šķīdība, reakcijas spēja utt.) un tos var viegli atdalīt, izmantojot minēto īpašību atšķirības. Diastereomēruš var nodalīt ar hromatogrāfiju vai, labāk, ar atdalīšanas/sašķelšanas metodēm, kas pamatojas uz šķīdības atšķirību. Tad reģenerē optiski tīru enantiomēru kopā ar atdalošo aģentu, izmantojot jebkādas praksē piemērotas metodes, kas' izslēgtu racemizāciju. Detalizētāks pārskats par metodēm, ko varētu izmantot savienojumu stereoizomēru iegūšanai no šo savienojumu racēmiskā maisījuma, minēts Jean Jacques Andre Collet, Samuel H. VVilen,[0154] Compounds of formula (I) can be prepared as individual stereoisomers of these compounds by subjecting the racemic mixture of these compounds to an optically active separation agent to form a diastereoisomeric pair, separating from the diastereomers and reducing the optically pure enantiomer. Although separation of enantiomers can be accomplished using covalent diastereoisomers of compounds of formula (I), dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. Diastereoisomers have distinct physical properties (eg melting point, boiling point, solubility, reaction capability, etc.) and can be easily separated by differences in these properties. The diastereomer can be separated by chromatography or, preferably, by separation / splitting methods based on the solubility difference. The optically pure enantiomer is then regenerated together with the separating agent using any suitable techniques that "exclude racemization. For a more detailed overview of the methods that could be used to obtain stereoisomers of compounds from the racemic mixture of these compounds, see Jean Jacques Andre Collet, Samuel H. VVilen.

Enantiomers, Racemates and Resolutions, John Wiley &amp; Sons, Inc. (1981). 46Enantiomers, Racemates and Resolutions, John Wiley &amp; Sons, Inc. (1981). 46

Bioloģisko preparātu pagatavošana [0155] Šo izgudrojumu realizējot praksē, izmantojami vairāki bioloģisko preparātu iegūšanas un attīrīšanas procesi. Bioloģisko preparātu pagatavošanas paņēmieni ir labi zināmi šajā jomā, kā aprakstīts turpmāk. - [0156] Monoklonālās antivielas var iegūt, izmantojot standarta paņēmienus, kas labi zināmi šajā jomā, tādas kā paņēmiens, kas aprakstīts Kohlerand Milstein, Nature 1975, 256:495 vai šī paņēmiena modifikācija, kā arī paņēmiens, kas aprakstīts Bucketal. 1982, Irt Vitro 18:377. Parasti peli vai žurku imunizē ar MenB PS atvasinājumu kopā ar proteīna nesēju, nonāvē un liesu (un neobligāti vairākus lielus limfmezglus) izņem un sadala atsevišķās šūnās. Ja vēlas, liesas šūnas var atsijāt (pēc nespecifisku pieguļošo šūnu nodalīšanas), šūnu suspensiju uzklājot uz plāksnītes vai dobītes, kas pārklāta ar antigēnu. B-šūnas, kas izpauž pret antigēnu specifisko, membrānas saistīto imunoglobulīnu, saistīsies ar plāksnīti un netiks noskalotas nost ar suspensijas paliekām. Rezultātā iegūtās B-šūnas vai visas sadalītās liesas šūnas pēc tam savienosies ar mielomas šūnām, veidojot hidridomas. Raksturīgākās peju mielomas līnijas, kas izmantojamas hidridizācijām, satur līnijas, kas pieejamas Amerikas Tipa kultūru kolekcijā (ATCC).Preparation of Biological Preparations [0155] In practice, a number of biological preparation and purification processes can be used in the practice of this invention. Techniques for preparing organic preparations are well known in the art, as described below. [0156] Monoclonal antibodies can be obtained using standard techniques well known in the art, such as the method described in Kohlerand Milstein, Nature 1975, 256: 495 or modification of this technique, as well as the technique described in Bucketal. 1982, Irt Vitro 18: 377. Usually, the mouse or rat is immunized with MenB PS derivative with the protein carrier, killed and spleen (and optionally several large lymph nodes) removed and divided into separate cells. If desired, the spleen cells can be screened (after separation of non-specific adherent cells) by applying a cell suspension on a plate or hollow coated with an antigen. B-cells that express antigen-specific membrane-bound immunoglobulin will bind to the plaque and will not be rinsed off with suspension residues. The resulting B-cells or all the split spleen cells then merge with myeloma cells to form hydridomas. Typical lines of myeloma for hydridation include lines available in the American Type Culture Collection (ATCC).

[0157] Himēriskās antivielas, kas sastāv no cilvēka un ne-ciivēka aminoskābju secībām, var iegūt no peļu monoklonālās antivielas molekulām, samazinot to imunogenitāti cilvēkos (VVinteretal Nature 1991 349:293; Lobugiioetal.Himeric antibodies consisting of human and non-human amino acid sequences can be derived from mouse monoclonal antibody molecules, reducing their immunogenicity in humans (Vinteretal Nature 1991 349: 293; Lobugiioetal.

Proc. Nat. Acad. ScL USA 1939 86:4220: Shaw et al. J. Immunol. 1987 138:4534; un Brown et al Cancer Res. 198747:3577; Riechmann et al. Nature 1988 332:323; Verboeyen et al. Science 1988 239:1534; un Jones et al.Proc. Nat. Acad. ScL USA 1939, 86: 4220: Shaw et al. J. Immunol. 1987 138: 4534; and Brown et al Cancer Res. 198747: 3577; Riechmann et al. Nature 1988 332: 323; Verboeyen et al. Science 1988 239: 1534; and Jones et al.

Nature 1986 321:522; EP ar publikācijas Nr.519, 596, publicēts 1992.gada, 23.decembrī; un U.K. patents ar publikācijas Nr. GB 2,276,169, publicēts 1994.gada 21.septembrī).Nature 1986 321: 522; EP with Publication No. 519, 596, published December 23, 1992; and U.K. patent with publication no. GB 2,276,169, published September 21, 1994).

[0158] Antivielas molekulas fragmentus, piemēram, F(ab')2, FV, un sFv molekulas, kas spēj izrādīt monoklonālās mātes antivielas molekulas. imunoloģiskās saistīšanas īpašības, var iegūt, izmantojot zināmus paņēmienus: Inbaretal. Proc. Nat. Acad. Sd. USA 1972 69:2659; Hochman etal Biochem. 1976 15:2706; Ehrlich et al Biochem. 1980 19:4091; Huston et al. Proc. Nat. Acad. Sd. USA 1988 85(16):5879,· un ASV patenti Nr. 5,091,513 un 5,132,405, un ASV patents Nr. 4,946,778.[0158] Fragments of the antibody molecule, such as F (ab ') 2, FV, and sFv molecules capable of displaying monoclonal parent antibody molecules. Immunological binding properties can be obtained using known techniques: Inbaretal. Proc. Nat. Acad. Sd. USA 1972 69: 2659; Hochman etal Biochem. 1976, 15: 2706; Ehrlich et al Biochem. 1980 19: 4091; Huston et al. Proc. Nat. Acad. Sd. USA 1988 85 (16): 5879, · and U.S. Pat. 5,091,513 and 5,132,405, and U.S. Pat. 4,946,778.

[0159] Alternatīvi fāgu uzrādīšanas sistēmu var izmantot, lai palielinātu monoklonālās antivielas molekulas populācijas irt vitro. Saiki, etal Nature 1986 324:163; Scharf et al Science 1986 233:1076; ASV patenti Nr. 4,683,195 un 4,683,202; Yang etal J. Mol. Biol 1995 254:392; Barbas, llletal Methods: Comp. Meth Enzymol 1995 8:94; Barbas, III etal. Proc. Nati. Acad.Alternatively, the phage display system can be used to increase the monoclonal antibody molecule populations in vitro. Saiki et al. Nature 1986 324: 163; Scharf et al Science 1986 233: 1076; U.S. Pat. 4,683,195 and 4,683,202; Yang et al. J. Mol. Biol 1995 254: 392; Barbas, Methods: Comp. Meth Enzymol 1995 8:94; Barbas, etal. Proc. Nati. Acad.

Sd. USA 1991 88:7978..Sd. USA 1991 88: 7978 ..

[0160] Kodējošās secības smagām un vieglām Fab molekulu ķēžu daļām, ko izvēlas no fāgu uzrādīšanas bibliotēkas, var izolēt vai sintezēt un klonēt jebkurā citā piemērotā vektorā vai replikā, kas piemērota, lai izpaustos. Var izmantot jebkuru izpausmes sistēmu, ieskaitot, piemēram, baktēriju, rauga, kukaiņu, amfībiju un zīdītāju izcelsmes sistēmas. Baktēriju izcelsmes 47 47 LV 13669 izpausmes sistēmas satur sistēmas, kas aprakstītas Chang etal Nature 1978 275:615, GoeddeJetal. Nature 1979281:544, Goeddeleta!NucleicAcids Res. 1980 8:4057, Eiropas pieteikums Nr. EP 36,776, ASVpatents Nr. 4,551,433, deBoer et al Proc. Nati. Acad. ScL USA 1983 80:21- 25, un Siebenlist et al Celi 198020:269.Coding sequences for heavy and light parts of Fab molecular chains selected from the phage display library can be isolated or synthesized and cloned into any other suitable vector or replica suitable for expression. Any expression system, including, for example, bacterial, yeast, insect, amphibious and mammalian systems can be used. The expression systems of bacterial origin 47 47 LV 13669 contain systems described in Chang et al Nature 1978 275: 615, GoeddeJetal. Nature 1979281: 544, Goeddeleta, NucleicAcids Res. 1980 8: 4057, European application no. EP 36,776, U.S. Pat. 4,551,433, deBoer et al. Proc. Nati. Acad. ScL USA 1983 80: 21-25, and Siebenlist et al., 198020: 269.

[0161] Rauga izcelsmes izpausmes sistēmas satur sistēmas, kas aprakstītas Hinnen etal Proc. Nati Acad. ScL USA 1978 75:1929, Ito etalJ. Bacteriol 1983 153:163, Kurtz etal Mol. Celi. Biol 1986 6:142, Kunze etal. J. Basic Microbiol. 198525:141, Gleeson eta/. J. Gen. Mlcroblol 1986 132:3459, Roggenkamp et al Mol. Gen. Genet. 1986202:302, Dasetal J. Bacteriol. 1984 158:1165, De Louvencourt et al J. Bacteriol. 1983 154:737, Vanden Berg etal. Bio/Technology 1990 8:135, Kunze etal. J. Basic Microbiol. 198525:141, Cregg etal. Mol. Celi. Biol. 1985 5:3376, ASV patentso Nr. 4,837,148 un 4,929,555, Beach etal. Nature 1981 300:706, Davidow et al. Curr. Genet. 1985 10:380, Gaillardin etalCurr. Genet. 1985 10:49, Ballance et al Biochem. Blophys. Res. Commun. 1983 112:284-289, Tilburn etal. Gene 1983 26:205-221, Yelton et ai Proc. Nati. Acad. Sd. USA 1984 81:1470-1474, KellyetalEMBOJ. 19854:475479; Eiropas pieteikumā Nr. EP 244,234, un Starptautiskā publikācijā Nr. WO 91/00357.Yeast expression systems contain systems described by Hinnen etal Proc. Nati Acad. ScL USA 1978 75: 1929, Ito et al. Bacteriol 1983 153: 163, Kurtz et al Mol. Great. Biol 1986 6: 142, Kunze et al. J. Basic Microbiol. 198525: 141, Gleeson et al. J. Gen. Mlcroblol 1986 132: 3459, Roggenkamp et al. Mol. Gen. Genet. 1986202: 302, Dasetal J. Bacteriol. 1984, 158: 1165, De Louvencourt et al., J. Bacteriol. 1983 154: 737, Vanden Berg et al. Bio / Technology 1990 8: 135, Kunze et al. J. Basic Microbiol. 198525: 141, Cregg et al. Mol. Great. Biol. 1985 5: 3376, U.S. Pat. 4,837,148 and 4,929,555, Beach etal. Nature 1981 300: 706, Davidow et al. Curr. Genet. 1985 10: 380, Gaillard et al. Genet. 1985 10:49, Ballance et al Biochem. Blophys. Res. Commun. 1983 112: 284-289, Tilburn et al. Gene 1983 26: 205-221, Yelton et al. Proc. Nati. Acad. Sd. USA 1984 81: 1470-1474, KellyetalEMBOJ. 19854: 475479; European application no. EP 244,234 and International Publication no. WO 91/00357.

[0162] Kukaiņu heteroloģisko gēnu izpausmi var panākt kā aprakstīts ASV patentā Nr. 4,745,051, Eiropas pieteikumos Nr. EP 127,839 un EP 155,476, VIak eta/. J. Gen. Virol. 1988 69:765-776, Miller et al Ann. Rev. Microbiol. 198842:177, Carbonell etal Gene 1988 73:409, Maeda etal Nature 1985 315:592-594, Lebacq-Verheyden et al Mol. Celi. Biol. 1988 8:3129, Smith et al Proc. Nati. Acad. Sd. USA 1985 82:8404, Miyajima etal Gene 198758:273, un Martin et al DNA 1988 7:99. Vairāki bakulovīrusu štami un varianti un attiecīgās ieteicamās kukaiņu saimnieka šūnas no saimniekiem aprakstītas Luckow et al Bio/Technology 1988 6:47-55, Miller et al GENETIC ENGINEERING, Setlow, J. K. et al eds., Vol. 8, Plenum Publlshing, pp. 1986277-279, un Maeda etal Nature 1985315:592-594.The expression of heterologous genes in insects can be achieved as described in U.S. Pat. 4,745,051, European applications no. EP 127,839 and EP 155,476, VIak et al. J. Gen. Virol. 1988 69: 765-776, Miller et al Ann. Rev. Microbiol. 198842: 177, Carbonell et al. Gene 1988 73: 409, Maeda et al. Nature 1985 315: 592-594, Lebacq-Verheyden et al. Mol. Great. Biol. 1988 8: 3129, Smith et al. Proc. Nati. Acad. Sd. USA 1985 82: 8404, Miyajima etal Gene 198758: 273, and Martin et al DNA 7:99. Several baculovirus strains and variants and the respective recommended host host cells are described in Luckow et al. Bio / Technology 1988 6: 47-55, Miller et al., GENETIC ENGINEERING, Setlow, J.K. et al eds., Vol. 8, Plenum Publlshing, p. 1986277-279, and Maeda etal Nature 1985315: 592-594.

[0163] Zīdītāju izcelsmes izpausmi var panākt kā aprakstīts Dijkema etal.. EMBO J. 1985 4:761, Gorman et al Proc. Nati. Acad. Sd. USA 1982 79:6777, Boshartetal Celi 1985 41:521, un ASV patentā Nr. 4,399,216. Citas zīdītāju izcelsmes izpausmes īpatnības var panākt kā aprakstīts Ham et al Meth. Enz. 1979 58:44, Barnes etalAnal. Biochem. 1980 102:255, ASV patentos Nr. 4,767,704, 4,657,866, 4,927,762, 4,560,655 an atkārtoti izdotā ASV patentāThe expression of mammalian expression can be achieved as described in Dijkema et al. EMBO J. 1985 4: 761, Gorman et al Proc. Nati. Acad. Sd. USA 1982 79: 6777, Boshartetal Keli 1985 41: 521, and U.S. Pat. 4,399,216. Other peculiarities of mammalian expression may be achieved as described by Ham et al Meth. Enz. 1979 58:44, Barnes et al. Biochem. 1980 102: 255, U.S. Pat. 4,767,704, 4,657,866, 4,927,762, 4,560,655 an re-issued US patent

Nr. RE 30,985, un Starptautiskās publikācijās Nr. WO 90/103430, WO 87/00195. .No. RE 30,985, and International Publication Nos. WO 90/103430, WO 87/00195. .

[0164] Rekombinanto adenovīrusu vektoru iegūšana aprakstīta ASV patentā Nr. 6,485,958.The production of recombinant adenoviral vectors is described in U.S. Pat. 6,485,958.

[0165] Botulīna toksīna “A” tipu var iegūt, Clostridium botulinum kultūras ievadot un audzējot fermentā un.pēc fermentācijas šo maisījumu savācot un attīrot saskaņā ar zināmām procedūrām. 48 [0166] Jebkuru no iepriekš minētajiem proteīnu iegūšanas paņēmieniem var izmantot bioloģiskā preparāta iegūšanai, kas varētu būt lietderīgs šī izgudrojuma ietvaros.The botulinum toxin type A can be obtained by administering and cultivating Clostridium botulinum cultures in an enzyme and collecting and purifying the mixture according to known procedures after fermentation. [0166] Any of the foregoing protein production techniques can be used to obtain a biological preparation that may be useful in the context of the present invention.

Farmakoloģija un pielietojamība [0167] Izgudrojumā aprakstītie savienojumi ir tādu cisteīna proteāžu selektīvie inhibitori, kā katepsīns S, K, B un/vai F, un it īpaši katepsīns S, un attiecīgi ir lietderīgi, ārstējot slimības, kurās cisteīna proteāzes aktivitātei ir loma slimības patoloģijā un/vai simptomatoloģijā. Piemēram, izgudrojumā aprakstītie savienojumi ir lietderīgi, ārstējot autoimūnos traucējumus, ieskaitot, bet ar minēto neierobežojoties, diabēta sākuma stāvoklī pusaudžiem, psoriāzi, izkliedēto sklerozi, pemphigus vulgaris, Greivza slimību, myasthenia grāvis, sistēmisko lupus erythemotasus, reimaioīdo artrītu un Flašimoto iiroidītu, alerģiskos traucējumus, ieskaitot, bet ar minēto neierobežojoties, astmu, alogēnās imūnās reakcijas, ieskaitot, bet ar minēto neierobežojoties, orgānu transplantus vai audu transplantus un endometriozi.Pharmacology and Applicability The compounds described in the invention are selective inhibitors of cysteine proteases such as cathepsin S, K, B and / or F, and in particular cathepsin S, and are therefore useful in the treatment of diseases in which cysteine protease activity plays a role in disease pathology. and / or symptomatology. For example, the compounds described in the invention are useful in the treatment of autoimmune disorders including, but not limited to, the onset of diabetes in adolescents, psoriasis, scattered sclerosis, pemphigus vulgaris, Grapefruit disease, myasthenia ditch, systemic lupus erythematosus, rheumatoid arthritis and Flusimoto iriditis, allergic disorders. including, but not limited to, asthma, allogeneic immune responses, including but not limited to, organ transplants or tissue transplants and endometriosis.

[0168] Katepsīns S ir iesaistīts arī traucējumos, kas saistīti ar pārmērīgu elastolīzi, tādu kā hroniskā obstruktīvā plaušu slimība (piemēram, emfizēma), bronholīts, pārmērīgā elpošanas ceju elastolīze astmas gadījumā un bronhīts, pneimonīts un kardiovaskulārā slimība, tāda kā plāksnīšu trūce un ateroma. Katepsīns S ir iesaistīts fibrilu veidošanās procesā un tāpēc katepsīna S inhibitori ir lietderīgi, ārstējot sistēmisko amiloidozi, [0169] Savienojumu ar formulu (I) cisteīna proteāzes inhibēšanas akiivitāti var noteikt ar paņēmieniem, kas zināmi šīs jomas speciālistiem ar parastu kvalifikācijas līmeni. In vitro eksperimenti, kas piemēroti proteāzes aktivitātes mērījumiem un proteāzes inhibēšanas noteikšanai, izmantojot testa savienojumus, ir zināmi. Parasti eksperimentā mēra· substrāta uz peptīda pamata hidrolīzi, ko izraisīja proteāze. Detalizēts eksperimentu pārskats par proteāzes inhibēšanas aktivitātes mērījumiem minēts Bioloģiskajos piemēros 1-5, infra.Cathepsin S is also involved in disorders associated with excessive elastolysis such as chronic obstructive pulmonary disease (eg, emphysema), bronchitis, excessive respiratory elastolysis in asthma, and bronchitis, pneumonitis, and cardiovascular disease such as plaque hernia and atherosclerosis. . Cathepsin S is involved in the formation of fibrils and therefore inhibitors of cathepsin S are useful in the treatment of systemic amyloidosis. The efficacy of cysteine protease inhibitors of formula (I) can be determined by techniques known to those of ordinary skill in the art. In vitro experiments suitable for the measurement of protease activity and for the detection of protease inhibition by test compounds are known. Typically, the experiment will measure the hydrolysis of the substrate to the peptide base caused by the protease. A detailed review of experiments on the measurement of protease inhibition activity in Biological Examples 1-5, infra.

Pielietošana un farmaceitiskas kompozīcijas [0170] Parasti savienojumi ar formulu (I) ievadāmi, lietojot terapeitiski efektīvu daudzumu jebkurā šajā jomā zināmā parastā un pieņemamā veidā un ievadot tikai šos savienojumus vai arī kombinācijā ar vienu vai vairākiem terapeitiskiem preparātiem. Terapeitiski efektīvs daudzums varētu būt ļoti dažāds atkarībā noelimības smaguma, pacienta vecuma un veselības stāvokļa, izmantojamā savienojuma potenciāla un citiem faktoriem.Uses and Pharmaceutical Compositions Compounds of formula (I) are generally administered by administering a therapeutically effective amount of any of the conventional and acceptable forms known in the art, and administering these compounds alone or in combination with one or more therapeutic agents. A therapeutically effective amount could vary widely depending on the severity of the condition, the age and health of the patient, the potential of the compound to be used, and other factors.

Piemēram, savienojuma ar formulu (I) terapeitiski efektīvidaudzumi var būt no 10 mikrogramiem uz ķermeņa svara kilogramu (pg/kg) dienā līdz aptuveni 100 miligramiem uz ķermeņa svara kilogramu (mg/kg) dienā, parasti no aptuveni. 100 pg/kg/dienā līdz aptuveni 10 mg/kg/dienā. Tādējādi, terapeitiski efektīvs daudzums cilvēkam ar 80 kg svaru var variēt no aptuveni 1 mg/dienā līdz aptuveni 8g/dienā, parasti no aptuveni 1 mg/dienā līdz aptuveni 800 mg/dienā. Parasti persona ar parastu kvalifikāciju šajā jomā, pamatojoties uz savām zināšanām un šajā pieteikumā aprakstīto, spēs noteikt savienojuma ar formulu (I) efektīvu daudzumu, ārstējot konkrētu slimību. 49 49 LV 13669 [0171] Savienojumus ar formulu (I) var ievadīt kā farmaceitiskas kompozīcijas vienā no šādiem veidiem: perorāli, sistēmiski (piemēram, transdermāli, intranazāli vai svecīšu veidā) vai arī parenterāli (piemēram, ievadot muskuļos, vēnās vai zemādas). Kompozīcijas var pagatavot tablešu, pilienu, kapsulu, puscietu preparātu, pulveru, preparātu ar ilgstošu aktīvās vielas izdalīšanos, šķīdumu, suspensiju, eliksīru, aerosolu veidā var jebkuras citas piemērotas kompozīcijas veidā un vispārējā gadījumā šīs kompozīcijas sastāv no savienojuma ar formulu (I) un vismaz vienas farmaceitiski pieņemamas pildvielas. Pieņemamas pildvielas ir netoksiskas, atbalsta ievadīšanu un negatīvi neietekmē aktīvās vielas terapeitisko labumu. Šādas pildvielas varētu būt cietas, šķidras, puscietas vai, aerosola kompozīcijas gadījumā, gāzveida, kas parasti ir pieejama personai ar kvalifikāciju šajā jomā.For example, therapeutically effective amounts of a compound of formula (I) may range from 10 micrograms per kilogram body weight (pg / kg) per day to about 100 milligrams per kilogram body weight (mg / kg) per day, usually about. 100 pg / kg / day to about 10 mg / kg / day. Thus, a therapeutically effective amount for a human 80 kg body weight may vary from about 1 mg / day to about 8 g / day, typically from about 1 mg / day to about 800 mg / day. Generally, a person with ordinary qualifications in this field, based on his or her knowledge and as described in this application, will be able to determine the effective amount of the compound of formula (I) for treating a particular disease. Compounds of formula (I) may be administered as pharmaceutical compositions in one of the following forms: oral, systemic (e.g., transdermal, intranasal, or suppository) or parenteral (e.g., by intramuscular, intravenous, or subcutaneous administration). Compositions can be prepared in the form of tablets, drops, capsules, semi-hard preparations, powders, formulations with sustained release of the active ingredient, solution, suspension, elixir, aerosol can be any other suitable composition, and in general these compositions consist of a compound of formula (I) and at least one pharmaceutically acceptable excipient. Acceptable fillers are non-toxic, support administration and do not adversely affect the therapeutic benefit of the active substance. Such fillers could be solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous, generally available to a person skilled in the art.

[0172] Cietās farmaceitiskās pildvielas satur cieti, celulozi, talku, glikozi, laktozi, saharozi, želatīnu, iesalu, rīsus, miltus, krītu, silīcija gelu, magnija stearātu, nātrija stearātu, glicerīna monostearātu, nātrija hlorīdu, žāvētu vājpienu un tamlīdzīgi. Šķidrās un pusšķidras pildvielas var izvēlēties no ūdens, eianola, glicerīna, propilēnglikola un dažādām eļļām, ieskaitot naftas, dzīvnieku, augu vai sintētiskās izcelsmes eļļas (piemēram, zemesriekstu eļļa, sojas pupu eļļa, minerāleļļa, sēžama sēklu eļļa un tamlīdzīgi). Labākie šķidrie nesēji, it īpaši injicējamiem šķīdumiem, ir ūdens, sāls šķīdums, dekstrozes un glikolu ūdens šķīdumi.Solid pharmaceutical fillers contain starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicon gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skimmed milk powder and the like. Liquid and semi-liquid fillers can be selected from water, ethanol, glycerol, propylene glycol and various oils including oil, animal, plant or synthetic (eg peanut oil, soybean oil, mineral oil, seed oil and the like). The best liquid carriers, especially for injectable solutions, are water, saline solution, dextrose and glycol aqueous solutions.

[0173] Savienojuma ar formulu (l) daudzums kompozīcijā var būt ļoti dažāds atkarībā no sastāva tipa, vienas devas daudzuma, pildvielas veida un citiem faktoriem, kas zināmi personām ar kvalifikāciju farmakoloģijas zinātnes jomā. Parasti savienojuma ar formulu (I) kompozīcija, kas paredzēta konkrētas slimības ārstēšanai, satur no 0.01% sv. līdz 90%sv., labāk no 5% sv. līdz 50% sv., aktīvās vielas un pārējais ir pildviela vai pildvielas. Labāk farmaceitiska kompozīcija ievadāma vienas devas veidā ilgstošas'ārstēšanas gadījumā vai kā viena deva pēc vēlēšanās, ja īpaši nepieciešama simptomu mazināšana. Raksturīgākie farmaceitisku savienojumu ar formulu (I) saturošo kompozīciju piemēri minēti turpmāk.[0173] The amount of the compound of formula (I) in the composition may vary widely depending on the type of composition, the amount of the single dose, the type of filler and other factors known to those skilled in the art of pharmacology. Typically, the composition of the compound of formula (I) for treating a particular disease comprises from 0.01% w / w to 5% w / v. up to 90% sv, better from 5% sv. up to 50% vol., active substances and the rest are filler or filler. A better pharmaceutical composition can be administered as a single dose in the case of long-term treatment or as a single dose if desired, in particular for the relief of symptoms. Typical examples of compositions containing pharmaceutical compounds of formula (I) are listed below.

Piemēri [0174] Turpmāk šis izgudrojums ilustrēts, bet ar minēto neierobežojoties, ar šādiem piemēriem, kas apraksta savienojumu ar formulu (I) (piemēri) un starpproduktu (atsauces) pagatavošanu saskaņā ar izgudrojumu. “A&quot; atsauce [0175] Trifluormetānsulfoskābes 2,2,2-trifluor-1 -(4-fluorfeņii)etilestera sintēzeEXAMPLES [0174] In the following, the present invention is illustrated but not limited by the following examples, which describe the preparation of compounds of formula (I) (Examples) and intermediates (references) according to the invention. “The &quot; reference Synthesis of trifluoromethanesulfonic acid 2,2,2-trifluoro-1- (4-fluorophenyl) ethyl ester

1.posms 50Stage 1 50

Samaisītam 2,2,2,4'-tetrafluoracetofenona (10 g, 52.1 mmoi) šķīdumam metanolā (50 mL) pievienoja NaBH4 (0.98 g, 26.5 mmol) temperatūrā 0° C. Pēc maisīšanas temperatūrā 25°C 2 stundu laikā reakciju pārtrauca, pievienojot 1N HCI (100 mL) un pēc tam ekstrahēja ar etilēteri. Ētera ekstraktu mazgāja ar sāls šķīdumu, žāvēja ar MgS04 un koncentrēja, iegūstot 2,2,2- trifluor-1-(4-fluorfenil)etanolu (11.32 g), ko bez turpmākas attīrīšanas izmantoja nākamajā posmā. 2. posmsTo a stirred solution of 2,2,2,4'-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBH 4 (0.98 g, 26.5 mmol) at 0 ° C. After stirring at 25 ° C for 2 hours, the reaction was stopped, 1N HCl (100 mL) was added and then extracted with ethyl ether. The ether extract was washed with brine, dried over MgSO 4 and concentrated to give 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol (11.32 g) which was used in the next step without further purification. Stage 2

NaH (640 mg, 16 mmol, 60% minerāieļļā) divas reizes skaloja ar heksānu (20 mL) un pēc tam pagatavoja suspensiju sausā dietilēterī (20 mL). Pievienoja 2,2)2-trifluor-1-(4-fluorfenil)etano!a (1.94 g, 10 mmoi) šķīdumu dietilēterī (10 mL) temperatūrā 0° C. Pēc maisīšanas 2 stundu laikā istabas temperatūrā pievienoja trifluormetānsulfonīla hlorīda (1.68 g, 10 mmol) šķīdumu dietilēterī (10 mL). Pēc divām stundām reakciju pārtrauca, pievienojot NaHG03 šķīdumu un produktu ekstrahēja ar dietilēterī. Ekstraktus skaloja ar sālsūdeni un žāvēja, un izņēma šķīdinātāju, iegūstot trifluormetānsulfoskābes 2,2,2-trifluor-1-(4-fluorfeni!)etilesteri (3.3 g). “B” atsauce 2,2,2-trifluor-l (7?)-(4-fluorfenil)etanola sintēzeNaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane (20 mL) and then slurried in dry diethyl ether (20 mL). A solution of 2.2) 2-trifluoro-1- (4-fluorophenyl) ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0 ° C. After stirring for 2 hours, trifluoromethanesulfonyl chloride (1.68 g) was added at room temperature. , 10 mmol) in diethyl ether (10 mL). After two hours, the reaction was quenched by addition of NaHGO 3 solution and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to give trifluoromethanesulfonic acid 2,2,2-trifluoro-1- (4-fluorophenyl) ethyl ester (3.3 g). Reference "B" Synthesis of 2,2,2-trifluoro-1 (7?) - (4-fluorophenyl) ethanol

[0176] 2,2,2,4- tetrafluoracetofenona šķīdumam (2.5 g, 13.01 mmol)toluolā (25 mL)/dihlormetānā (25 mL) temperatūrā -78°C un 1M S-metil-CBS-oksazaborolidīna katalizatora klātbūtnē (1.3 mL, 1.3 mmol) pievienoja svaigi destilētu kateholborānu (1.66.mL, 15.62 mmol). Reakcijas maisījumu uzturēja temperatūrā -78°C 16 stundas, šajā laikā pievienoja 4N HCI (5 mL dioksānā) un reakcijas maisījumu atstāja uzsilt līdz istabas temperatūrai. Reakcijas maisījumu atšķaidīja ar etilacetātu un skaloja ar piesātinātu sāls šķīdumu. Organisko kārtu žāvēja virs magnija sulfāta, filtrēja un koncentrēja, iegūstot nogulsni. Cieto nogulsni suspendēja heksānos un nofiltrēja. Heksānu filtrētu, kas saturēja vēlamo produktu, koncentrēja un atlikumu pakļāva flešhromatogrāfijai (10 heksāni: 1 etilacetāts), iegūstot izgudrojumā aprakstīto savienojumu bezkrāsainas eļļas veidā (2.2g, 87% iznākums). Noteica, ka enantiomēru saturs ir 95:5 pēc hirālās šķidruma hromatogrāfijas (Chiralcel OD kolonna, mobilā fāze 95 heksāni: 5 izopropanols. Galvenā produkta aiztures laiks 6.757 min. Mazākā izomēra aiztures laiks 8.274 min.). D” atsauce 2(R)-[2,2,2-trifluor-1(5)-(4-fluorfenil)etilamino]-3-tritilsu!fanīlpropānskābes sintēzeTo a solution of 2,2,2,4-tetrafluoroacetophenone (2.5 g, 13.01 mmol) in toluene (25 mL) / dichloromethane (25 mL) at -78 ° C and 1M S-methyl-CBS-oxazaborolidine catalyst (1.3 mL) , 1.3 mmol) was added freshly distilled catechol borane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at -78 ° C for 16 hours, at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a precipitate. The solid precipitate was suspended in hexanes and filtered. Filtration of the hexane containing the desired product was concentrated and the residue was subjected to flash chromatography (10 hexanes: 1 ethyl acetate) to give the title compound as a colorless oil (2.2g, 87% yield). The enantiomer content was determined to be 95: 5 by chiral liquid chromatography (Chiralcel OD column, mobile phase 95 hexanes: 5 isopropanol. Main product retention time 6,757 min. Minimum isomer retention time 8.274 min.). Reference D 'Synthesis of 2 (R) - [2,2,2-Trifluoro-1- (5) - (4-fluorophenyl) ethylamino] -3-tritylpiperylpropanoic acid

51 LV 13669 [0177] Lai suspendētu S-tritil-L-cisteīnu (4.86 g, 13.37 mmol) dihlorometānā (97 mL, 20 mL/g AA) istabas temperatūrā, pievienoja diizopropiletilamīnu (9.32 mL, 53.48 mmol), kam sekoja trifluormetānulfonskābes 2,2,2-trifluor-1(/?S)-feniletilestera (5.32 g, 16.04 mmol) (galvenais enantiomērs (S), 90 ee) šķīdumu dihlormetānā pievienošana aršjirci vienā paņēmienā. Pēc 19 stundām reakcijas maisījumu koncentrēja ar rotovapu, iegūstot eļļu. Pievienoja dietilēteri un šķīdumu skaloja ar 1N HCI un sālsūdeni. Organisko kārtu žāvēja virs MgSCU, filtrēja un koncentrēja. Veicot atlikuma flešhromatogrāfiju, kā eluentu izmantojot 2 heksāni/1 etilacetāts/.25% etiķskābi, ieguva 2(/7)-[2,2,2-trifluor-1(RS)-(4-fluorfenil)etilamino]-3-tritilsulfanilpropānskābi (6 g) (galveno diastereomēru (R,S), 90 de) eļļas/putu veidā. Έ” atsauce 2-(1-aminociklopropil)-N-ciklopropil-2-hidroksiacetamīda sintēzeTo suspend S-trityl-L-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL / g AA) at room temperature, diisopropylethylamine (9.32 mL, 53.48 mmol) was added followed by trifluoromethanesulfonic acid 2. The addition of 2,2-trifluoro-1 (S) -phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) to dichloromethane solutions in an arachis in one step. After 19 hours, the reaction mixture was concentrated on rotovap to give an oil. Diethyl ether was added and the solution was washed with 1N HCl and brine. The organic layer was dried over MgSO 4, filtered and concentrated. Purification by flash chromatography using 2 hexanes / 1 ethyl acetate / 25% acetic acid as eluant gave 2 (t) - [2,2,2-trifluoro-1 (RS) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid (6 g) (major diastereomers (R, S), 90 de) in the form of oil / foam. Uce ”Reference Synthesis of 2- (1-Aminocyclopropyl) -N-cyclopropyl-2-hydroxyacetamide

1.posms [0178] 1-aminociklopropānkarbonitrila hlorhidrātu (6.1 g, 51.4 mmol) maisīja ar 6N sālsskābi (500 mL) 7 stundu laikā un pēc tam koncentrēja, iegūstot 1-aminociklopropānkarboksilskābes hlorhidrātu kā pelēkbaltu cietu vielu, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 2.posms [0179] 1-aminociklopropānkarboksilskābes hiorhidrāta (3.6 g, 26.2 mmol) šķīdumu MeOH (100 mL) kālija karbonāta klātbūtnē (4.0 g, 28.94 mmol) maisīja istabas temperatūrā 48 stundu laikā. Pēc filtrācijas MeOH izņēma pazeminātā spiedienā, iegūstot 1- aminociklopropānkarboksilskābi (2.64 g), ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 3.posms [0180] 1-aminociklopropānkarboksilskābi (2.64 g, 26.1 mmol) un tetrametifamonija hidroksīdu (2.38 g, 26.1 mmol) pievienoja acetonitrilam (150 mL). Reakcijas maisījums kļuva homogēns pēc maisīšanas istabas temperatūrā aptuveni stundas laikā. Pēc tam pievienoja Boc20 (8.54 g, 39.2 mmol) un maisīšanu turpināja 2 dienu laikā. 3.dienā pievienoja vēl vienu Boc20 devu (2.85 g, 13.1 mmol) un reakcijas maisījumu maisīja vēl vienu dienu. Acetonitrilu izņēma pazeminātā spiedienāun atlikumu sadalīja starp H20 un Et20. Ūdens kārtu mazgāja ar Et20 un pēc tam pievienoja cieto citronskābi līdz pH ~3. Ūdens šķīdumu ekstrahēja ar EtOAc. Apvienotos EtOAc ekstraktus skaloja ar sālsūdeni, žāvēja (Na2S04) un EtOAc izņēma pazeminātā spiedienā, iegūstot 1-tercbutoksikarbonilaminociklo-propānkarboksilskābi baltas nogulsnes veidā (2.32 g), ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 4.posms 52 [0181] 1-tercbutoksikarbonilaminociklopropānkarboksilskābes (2.32 g, 11.5 mmol) šķīdumam CH2CI2 (25 mL) temperatūrā 0°C pievienoja N,0-dimetilhidroksilamīna hidrohlorīdu (1.24 g, 12,7 mmol), trietiiamīnu (2.57 g, 3.54 mL, 25.4 mmol) un HATU (4.82 g, 12.7 mmol). Reakcijas maisījumu maisīja istabas temperatūrā 4 stundas. Reakcijas maisījumu koncentrēja pazeminātā spiedienāun pēc tam sadalīja starp Et20 un ūdeni. Ūdens kārtu ekstrahēja ar Et20. Apvienoto organisko kārtu mazgāja ar sālsūdeni, žāvēja (Na2S04) un koncentrēja pazeminātā spiedienā, iegūstot [1-(metoksimeti!karbamoil)ciklopropil]karbāmskābes tercbutilesteri, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 5.posms [0182] [1-(metoksimetilkarbamoil)ciklopropil]karbāmskābes tercbutilestera 0.05 M šķīdumam Et20 (80 mL, 4.0 mmol) istabas temperatūrā pilinot pievienoja litija alumīnija hidrīdu (1.0 M Et20, 5 mL, 5.0 mmol). Reakcijas maisījumu maisīja vēl 20 minūtes un pēc tam reakciju pārtrauca, pievienojot 6 mL KHSO4 ūdens šķīdumā. Kārtas nodalīja un ūdens kārtu ekstrahēja ar Et20. Apvienotās organiskās kārtas mazgāja ar 1 N HCI, piesātināto NaHCOs un sāls šķīdumu, žāvēja (Na2S04) un koncentrēja, iegūstot (1-formilciklo-propil)karbāms.kābes tercbutilesteri bezkrāsainas eļļas veidā (393 mg), ko bez turpmākas tīrīšanas tūlīt izmantoja nākamajā posmā. 6. posms [0183] (l-formiiciklociklopropil)karbāmskābes tercbutilestera (393 mg, 2.12 mmol) šķīdumam CH2C!2 (4 mL) pievienoja etiķskābi (191 mg, 0.182 mL, 3.18 mmol) un ciklopropiiizocianīdu (142 mg, 2.12 mmol). Reakcijas maisījumu maisīja vienu nakti istabas temperatūrā un pēc tam koncentrēja pazeminātā spiedienā, iegūstot jēlo etiķskābes (1-tercbutoksikarbonilamino-ciklopropil)ciklopropilkarbamoilmetilesteri, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. ' 7. posms [0184] Etiķskābes (1-tercbutoksikarbonilaminociklopropil) ciklopropilkarbamoil-metilestera šķīdumam MeOH (5 mL) pievienoja 10% NaOH (1 mL). Reakcijas maisījumu maisīja istabas temperatūrā 2 stundas un pēc tam pievienoja 2.5N HCI līdz pH 7. Šķīdumu ekstrahēja ar EtOAc, skaloja arsālūdeni, žāvēja (Na2S04) un koncentrēja pazeminātā spiedienā, iegūstot [1-(ciklopropilkarbamoilhidroksimetil)cikIopropil]karbāmskābes tercbutilesteri dzeltenas eļļas veidā, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 8.posms [0185] [1-(ciklopropilkarbamoilhidroksimetil)ciklopropil]karbāmskābes tercbutilestera šķīdumu CH2CI2 (5 mL) un TFA (5 mL) maisīja istabas temperatūrā 2.5 stundas. Reakcijas maisījumu koncentrēja un atšķaidīja ar toluolu, iegūstot 2-(1-aminociklopropil)-N-ciklopropil-2-hīdroksiacetamīdu.Stage 1 1-Aminocyclopropanecarbonitrile Chlorohydrate (6.1 g, 51.4 mmol) was stirred with 6N hydrochloric acid (500 mL) over 7 hours and then concentrated to give 1-aminocyclopropanecarboxylic acid hydrochloride as a off-white solid which was used in the next step without further purification . Step 2: A solution of 1-aminocyclopropanecarboxylic acid hydrochloride (3.6 g, 26.2 mmol) in MeOH (100 mL) in the presence of potassium carbonate (4.0 g, 28.94 mmol) was stirred at room temperature for 48 hours. After filtration, MeOH was removed under reduced pressure to give 1-aminocyclopropanecarboxylic acid (2.64 g) which was used in the next step without further purification. Step 3: 1-Aminocyclopropanecarboxylic acid (2.64 g, 26.1 mmol) and tetramethifammonium hydroxide (2.38 g, 26.1 mmol) were added to acetonitrile (150 mL). The reaction mixture became homogeneous after stirring at room temperature for about an hour. Boc20 (8.54 g, 39.2 mmol) was then added and stirring continued for 2 days. On day 3, another Boc20 dose (2.85 g, 13.1 mmol) was added and the reaction mixture was stirred for another day. Acetonitrile was removed under reduced pressure and the residue partitioned between H 2 O and Et 2 O. The water layer was washed with Et2O and then solid citric acid was added to pH ~ 3. The aqueous solution was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na 2 SO 4) and EtOAc under reduced pressure to give 1-t-butoxycarbonylaminocyclo-propanecarboxylic acid as a white precipitate (2.32 g) which was used in the next step without further purification. Step 4 52 To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH 2 Cl 2 (25 mL) at 0 ° C was added N, O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol), triethylamine (2.57 g, 3.54). mL, 25.4 mmol) and HATU (4.82 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then partitioned between Et 2 O and water. The water layer was extracted with Et2O. The combined organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give [1- (methoxymethylcarbamoyl) cyclopropyl] carbamic acid tert-butyl ester which was used in the next step without further purification. Stage 5 [1- (Methoxymethylcarbamoyl) cyclopropyl] carbamic acid tert-butyl ester 0.05 M solution of Et 2 O (80 mL, 4.0 mmol) was added dropwise at room temperature by lithium aluminum hydride (1.0 M Et 2 O, 5 mL, 5.0 mmol). The reaction mixture was stirred for an additional 20 minutes and then quenched by addition of 6 mL KHSO4 in aqueous solution. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with 1 N HCl, saturated NaHCO 3, and brine, dried (Na 2 SO 4) and concentrated to give (1-formylcyclo-propyl) carbamate acid tert-butyl ester as a colorless oil (393 mg) which was immediately used in the next step without further purification . Step 6 To a solution of (1-formicycloocyclopropyl) carbamic acid tert-butyl ester (393 mg, 2.12 mmol) in CH 2 Cl 2 (4 mL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol) and cyclopropylisocyanide (142 mg, 2.12 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give the crude acetic acid (1-tert-butoxycarbonylamino-cyclopropyl) cyclopropylcarbamoylmethyl ester which was used in the next step without further purification. Step 7: To a solution of acetic acid (1-t-butoxycarbonylaminocyclopropyl) cyclopropylcarbamoylmethyl ester in MeOH (5 mL) was added 10% NaOH (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then 2.5N HCl was added to pH 7. The solution was extracted with EtOAc, rinsed with brine, dried (Na2SO4) and concentrated under reduced pressure to give [1- (cyclopropylcarbamoylhydroxymethyl) cyclopropyl] carbamic acid tert-butyl ester as a yellow oil. which was used in the next stage without further cleaning. Stage 8 [1- (Cyclopropylcarbamoylhydroxymethyl) cyclopropyl] carbamic acid tert-butyl ester solution in CH2Cl2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and diluted with toluene to give 2- (1-aminocyclopropyl) -N-cyclopropyl-2-hydroxyacetamide.

[0186] Rīkojoties kā aprakstīts iepriekš 3.-8.posmā, bet 1-aminociklopropānkarboksilskābi aizvietojot ar 1-aminocikloheksānkarboksil-skābi, iegūst 2-(1-aminocikloheksil)-N-ciklopropil-2-hīdroksiacetamīdu. 53 53 LV 13669 T&quot; atsauce 3-amino-N-ciklopropil-2-hidroksi-3-metilbutiramida sintēzeProceeding as described in steps 3 to 8 above, and replacing 1-aminocyclopropanecarboxylic acid with 1-aminocyclohexanecarboxylic acid affords 2- (1-aminocyclohexyl) -N-cyclopropyl-2-hydroxyacetamide. 53 53 EN 13669 T &quot; Reference Synthesis of 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide

1.posms [0187] (2-hidroksi-1l1-dimetiletil)karbāmskābes tercbutilestera (284 mg, 1.5 mmol) šķīdumam CH2CI2 (5 ml) pievienoja Dess-Martin perjodānu (763 mg, 1.8 mmol) temperatūrā 0°C. Pēc 1.5 stundas pievienoja 0.26M Na2S203 šķīdumu piesātinātā NaHC03 (6 mL) un šo maisījumu maisīja 15 min. Kārtas nodalīja un ūdens kārtu ekstrahēja ar CH2CI2. Apvienotās organiskās kārtas žāvēja (Na2S04) un koncentrēja, iegūstot (1,1 -dimetil-2-okso-etil) karbāmskābes iercbutilesteri baltas nogulsnes veidā, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 2. posms [0188] (1,1-dimeril-2-okso-etil)karbāmskābes tercbutilestera šķīdumam' CH2CI2 pievienoja etiķskābi (180 mg, 0.172 mL, 3.0 mmol) un ciklopropilizocianīdu (101 mg, 1.5 mmol). Reakcijas maisījumu maisīja pa nakti istabas temperatūrā un pēc tam koncentrēja, iegūstot jēlo etiķskābes 2-tercbutoksikarbonilamino-1-ciklopropilkarbamoil-2-metilpropilesteri, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 3. posms [0189] Etiķskābes 2-tercbutoksikarbonilamino-1 -ciklopropilkarbamoil-2-metilpropilestera šķīdumam MeOH (10 mL) pievienoja 10% NaOH (1.5 mL). Reakcijas maisījumu maisīja istabas temperatūrā 3 stundu laikā un pēc tam pievienoja 1N sālsskābi līdz pH 7. Reakcijas maisījumu ekstrahēja ar EtOAc. Organisko kārtu žāvēja (Na2S04) un koncentrēja, iegūstot (2-ciklopropil-karbamoil-2-hidroksi-1,1-dimeii!etil)karbāmskābes tercbutilesteri, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 4. posms [0190] (2-ciklopropīikarbamoii-2-hidroksi-1,1-dimetiletil)karbāmskābes tercbutilestera šķīdumu CH2CI2 (10 mL) un TFA (5 mL) maisīja istabas temperatūrā 4 stundas. Pēc tam reakcijas maisījumu koncentrēja un atšķaidīja, iegūstot 3-amino-N- ciklopropil-2-hidroksi-3-metilbutiramīdu. “G” atsauce 3-amino-N-benzil-2-hidroksi-3-metilbutiramīda sintēzeStep 1 To a solution of (2-hydroxy-11-dimethylethyl) carbamic acid tert-butyl ester (284 mg, 1.5 mmol) in CH 2 Cl 2 (5 mL) was added Dess-Martin periodan (763 mg, 1.8 mmol) at 0 ° C. After 1.5 hours, 0.26M Na2S2O3 solution was added to saturated NaHCO3 (6 mL) and the mixture was stirred for 15 min. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2. The combined organic layers were dried (Na 2 SO 4) and concentrated to give (1,1-dimethyl-2-oxo-ethyl) carbamic acid tert-butyl ester as a white precipitate which was used in the next step without further purification. Step 2 To a solution of (1,1-dimethyl-2-oxo-ethyl) -carbamic acid tert-butyl ester 'CH 2 Cl 2 was added acetic acid (180 mg, 0.172 mL, 3.0 mmol) and cyclopropylisocyanide (101 mg, 1.5 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated to give the crude acetic acid 2-t-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester which was used in the next step without further purification. Step 3 To a solution of 2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester of acetic acid was added 10% NaOH (1.5 mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 3 hours and then 1N hydrochloric acid was added to pH 7. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na 2 SO 4) and concentrated to give (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester which was used in the next step without further purification. Step 4: A solution of (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl) carbamic acid tert-butyl ester in CH2Cl2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 hours. The reaction mixture was then concentrated and diluted to give 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide. Reference "G" Synthesis of 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide

54 [0191] 3-amino-N-benzil-2-hidroksi-3-metilbutiramīdu pagatavoja saskaņā ar 3-amino-N'Cik!opropil-2-hidroksi-3-metilbutiramīda iegūšanas procedūru, ciklopropilizocianīdu aizvietojot ar benziiizocianīdu. 1.piemērs 2-okso-3(S)-{3-(piridin-3-ilmetānsulfonil)-2(R)-[2,2,2-trifluor-1(S)-(4-fIuorfeni[)etilamino]-propionilamino}heksānskābes ciklopropīlamīda sintēze[0191] 3-Amino-N-benzyl-2-hydroxy-3-methylbutyramide was prepared according to the procedure for obtaining 3-amino-N'-cyclopropyl-2-hydroxy-3-methylbutyramide by replacing cyclopropylisocyanide with benzylisocyanide. Example 1 2-Oxo-3 (S) - {3- (pyridin-3-ylmethanesulfonyl) -2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -propionylamino} hexanoic acid cyclopropylamide synthesis

1.posms [0192] Kateholborāna (19.4 mL, 182 mmol) šķīdumu dinlormetānā (15 mL) pievienoja S-meiil CBS oksazaboroiidīna (13 mL, 13 mmol) un 2,2,2,4-ietrafluoracetofenona (18.2 mL, 130.13mmo!) šķīdumam dihlormetānā, pilinot temperatūrā -78°C 30 minūšu laikā, Reakcijas maisījumu maisīja -78°C vienu nakti. Reakciju pārtrauca ar4N HCI (13 mL) dioksānā -78°C, sasildīja līdz istabas temperatūrai un šķīdinātāju izņēma pazeminātā spiedienā. 10% NaHS03 šķīdumu (200 mL) pievienoja koncentrātam un ūdens kārtu ekstrahēja ar heksānu. Ograņisko kārtu skaloja ar ūdeni un žāvēja ar MgS04. Šķīdinātāju izņēma pazeminātā spiedienā, iegūstot.2,2,2-irifluor-1(R)-(4-i!uorfenīl)etanolu (20 g) bezkrāsainas eļļas veidā (90% e.e.). 2.posms [0193] NaH (11.87 g, 296.7mmol) pievienoja Et20 (700 mL) temperatūrā 0°C N2 atmosfērā, pēc tam pievienoja 2,2,2-trifluor-1(R)-(4-fluorfenil)etanola (44.3g, 228.2 mmol) šķīdumu Et20. Reakcijas maisījumu maisīja 10 miri. 0°C, pēc tam 1 stundu istabas temperatūrā. Trifluormetānsulfonilhlorīda (50 g, 296.7 mmol) šķīdumu Et20 pievienoja 0°C N2 atmosfērā un reakcijas maisījumu maisīja 10 min. temparetūrā 0°C un pēc tam 3 stundas istabas temperatūrā. Šķīdinātāju izņēma pazeminātā spiedienā un lēnām pievienoja H20 (100 mL). Ūdens kārtu ekstrahēja ar heksānu un apvienoto organisko kārtu žāvēja ar MgSOz*. Šķīdinātāju izņēma pazeminātā spiedienā, iegūstot trifluormetānsulfonskābes 2,2,2-trifluor- 1(R)-(4-fluorfeni!)etīlesteri (70 g) bezkrāsainas eļļas veidā. 3.posms [0194] 2(/?)-amino-3-tritiisulfanilpropānskābi (78 g, 214.6mmol) šķīdināja CH2CI2, pievienoja DIPEA (112 mL, 643.8mmol) un reakcijas maisījumu maisīja 10 minūtes istabas temperatūrā. Pievienoja trifluormetānsulfonskābes 55 55 LV 13669 2,2,2-trifluor- 1(H)-(4-fluorfenii)etilestera (70 g, 214.6mmol) un CH2CI2 maisījumu un reakcijas maisījumu maisīja pa nakti istabas temperatūrā. Šķīdinātāju izņēma pazeminātā spiedienā un atlikumu šķīdināja Et20 un skaloja ar 1N HCI un sālsūdeni un žāvēja uz MgS04. Izņēma šķīdinātāju, iegūstot 2(R)-[2,2,2-trifluor-1(S)-(4-fluorfenil)etilamino]-3-tritilsulfanilpropānskābi (90 g) dzeltenas cietas vielas veidā. 4.posms [0195] 2(F?)~[2,2,2-trifluor-1 (S)-(4-fluorfenil)etilamino]-3-tritilsulfanilpropānskābi (5.4 g, 10 mmol) šķīdināja CH2CI2 un pievienoja TFA (3.1 mL, 40 mmol) 0°C N2 atmosfērā. Et3SiH (3.2 mL, 20mmo!) pievienoja 0°C N2 atmosfērā un reakcijas maisījumu sasildīja līdz istabas temperatūrai. Pēc maisīšanas 2 stundu laikā šķīdinātāju izņēma pazeminātā spiedienā un atlikumu šķīdināja 1N NaOH (120 ml). Ūdens kārtu ekstrahēja arfieksānu. Ūdens šķīdumam pievienoja dioksānu (120 mL), 3-pikolilhlorīda hldrohlorīdu (1.97g, 12 mmol), un tris(2-karboksietil)fosfina hidrohlorīdu (280 mg, 1 mmol). Reakcijas maisījumu maisīja istabas temperatūrā vienu nakti. Dioksānu izņēma pazeminātā spiedienā. Ūdens kārtas pH regulēja līdz pH3 un ekstrahēja ar etilacetātu. Apvienoto organisko kārtu žāvēja virs MgSCL, filtrēja un koncentrēja pazeminātā spiedienā, iegūstot 3-(piridin-3-ilmetānsulfanil)-2(R-)* [2,2,2-frifluor-1(S)-(4-fluorfenii)-eti!amino]propānskāb!, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 5.posms [0196] 3-(piridin-3-ilmetānsulfanil)-2(R-)-[2,2,2~trifluor-1(S)-(4-fluonenil)-etilaminojpropānskābes šķīdumam metanolā (10 mL) pievienoja ΟΧΟΝΕ® (4.68g, 15 10 mL H20) ūdens šķīdumu. Reakcijas maisījumu maisīja istabas temperatūrā. Pēc 2 stundām šķīdinātāju izņēma pazeminātā spiedienā. Ūdens kārtu ekstrahēja ar etilacetātu un apvienotās organiskās kārtas skaloja ar sālsūdeni un žāvēja virs MgSŪ4 un filtrēja. Filtrētu koncentrēja pazeminātā spiedienā, iegūstot 3-(piridin-3-i!metānsulfonil)-2-(/7)[2,2,2-irifluor-1 (S)-(4-fluorfenil)etilamino]propānskābi, ko bez turpmākas tīrīšanas izmantoja nākamajā posmā. 6.posms [0197] Pagatavoja 3-(pirīdin-3-iImetānsulfonil)-2-(/:?)[2J2,2-trifiuor-1 (S)-(4-fluorfenil)etilamino] propānskābes (420 mg, 1 mmol) un 3(S)-amino-2-hidroksiheksānskābes ciklopropilamīda (186 mg, 1 mmol) maisījumu kā aprakstīts PCT pieteikuma publikācijā Nr. VVO-02/18369, - kā savienojumu xiii, kam pievienoja HBTU (455 mg, 1.2 mmol) un NMM ( 0.44mL, 4 mmol) acetonitrilā un maisīja istabas temperatūrā vienu nakti. Pievienoja piesātinātu NH4CI (10 mL) un etilacetātu (10 mL) un pēc 20 minūtēm ūdens kārtu ekstrahēja ar etilacetātu. Apvienotos organiskos ekstraktus skaloja ar sālsūdeni un žāvēja ar MgS04, filtrēja un filtrētu koncentrēja pazeminātā · spiedienā, iegūstot 2-hidroksi-3(S)-{3-(piridin-3-ilmetānsulfonil)-2(R)'[2,2,2-trifluor-1($)-(4-fluorfenil)-etilamino]propionilamino}heksānskābes ciklopropilamīdu, ko bez turpmākas tīrīšanas izmantoja, nākamajā posmā. 7.posms 56 [0198] 2-hia'roksī-3(S)-{3-(piridin-3riimetānsulfonn)-2(R)-[2l2,2-trif!uor-1 (5)-(4-fluorfenil)-etilamino]propionilamino}heksānskābes ciklopropilamīda (590 mg, 1 mmol) šķīdumam metilēnhloffdā lēnām pievienoja DMP. Reakcijas maisījumu maisīja istabas temperatūra 30 minūtes un pēc tam pievienoja 0.26 M Na2S203 piesātinātajā NaHC03. Reakcijas maisījumu maisīja 20 minūtes. Ūdens kārtu ekstrahēja ar metilēnhiorīdu un apvienotos organiskos ekstraktus žāvēja uz MgS04, filtrēja un koncentrēja, iegūstot 2-okso-3(S)-{3-(piridin-3-ilmetānsulfonil)-2(R)-[2,2,2-trifluor-1(S)-(4- fluorfeniljetilamino]-propionilaminojheksānskābes ciklopropilamīdu, ko tīrīja fleškolonnā (2% MeOH-CH2CI2), iegūstot tīru produktu dzeltenas cietas vielas veidā.Step 1 A solution of catechol borane (19.4 mL, 182 mmol) in dichloromethane (15 mL) was added to S-methyl CBS oxazaborolidine (13 mL, 13 mmol) and 2,2,2,4-cis-fluoroacetophenone (18.2 mL, 130.13mmo!). ) at a temperature of -78 ° C for 30 minutes, the reaction mixture was stirred at -78 ° C overnight. The reaction was quenched with 4N HCl (13 mL) in dioxane at -78 ° C, warmed to room temperature and the solvent removed under reduced pressure. 10% NaHSO3 solution (200 mL) was added to the concentrate and the aqueous layer was extracted with hexane. The green layer was washed with water and dried over MgSO4. The solvent was removed under reduced pressure to give.2,2,2-irifluoro-1 (R) - (4-fluorophenyl) ethanol (20 g) as a colorless oil (90% e.e.). Step 2: NaH (11.87 g, 296.7 mmol) was added to Et 2 O (700 mL) at 0 ° C under N 2, then 2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethanol was added ( 44.3g, 228.2 mmol) of Et2O solution. The reaction mixture was stirred for 10 l. 0 ° C, then 1 hour at room temperature. A solution of trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) in Et 2 O was added at 0 ° C under N 2 and the reaction mixture was stirred for 10 min. at 0 ° C and then for 3 hours at room temperature. The solvent was removed under reduced pressure and H 2 O (100 mL) was added slowly. The aqueous layer was extracted with hexane and the combined organic layer was dried over MgSO 4. The solvent was removed under reduced pressure to give trifluoro-methanesulfonic acid 2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethyl ester (70 g) as a colorless oil. Step 3: 2 (β) -amino-3-tritylsulfanylpropanoic acid (78 g, 214.6 mmol) was dissolved in CH 2 Cl 2, DIPEA (112 mL, 643.8 mmol) was added and the reaction mixture was stirred for 10 minutes at room temperature. Trifluoromethanesulfonic acid 55 55 LV 13669 2,2,2-trifluoro-1 (H) - (4-fluorophenyl) ethyl ester (70 g, 214.6 mmol) and CH 2 Cl 2 were added and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in Et2O and washed with 1N HCl and brine and dried over MgSO 4. The solvent was removed to give 2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid (90 g) as a yellow solid. Step 4: 2 (F) - [2,2,2-Trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid (5.4 g, 10 mmol) was dissolved in CH 2 Cl 2 and added to TFA ( 3.1 mL, 40 mmol) at 0 ° C under N 2. Et 3 Si (3.2 mL, 20 mL) was added at 0 ° C under N 2 and the reaction mixture was warmed to room temperature. After stirring for 2 hours, the solvent was removed under reduced pressure and the residue was dissolved in 1N NaOH (120 mL). The water layer was extracted with arphexane. To the aqueous solution was added dioxane (120 mL), 3-picolyl chloride hydrochloride (1.97 g, 12 mmol), and tris (2-carboxyethyl) phosphine hydrochloride (280 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. Dioxane was removed under reduced pressure. The pH of the water layer was adjusted to pH3 and extracted with ethyl acetate. The combined organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure to give 3- (pyridin-3-ylmethanesulfonyl) -2 (R -) * [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) - Ethylamino] propane acid, which was used in the next step without further purification. Step 5: To a solution of 3- (pyridin-3-ylmethanesulfonyl) -2 (R -) - [2,2,2-trifluoro-1 (S) - (4-fluoronyl) -ethylamino] propanoic acid in methanol (10 mL) ΟΧΟΝΕ® (4.68 g, 10 10 mL H 2 O) aqueous solution. The reaction mixture was stirred at room temperature. After 2 hours, the solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 3- (pyridin-3-ylmethanesulfonyl) -2 - ((7) [2,2,2-irifluoro-1 (S) - (4-fluorophenyl) ethylamino] propanoic acid, which was used without further purification. cleaning was used in the next stage. Step 6: 3- (Pyridine-3-ylmethanesulfonyl) -2- (1 H) -2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] propanoic acid (420 mg, 1 mmol) ) and a mixture of cyclopropylamide (186 mg, 1 mmol) of 3 (S) -amino-2-hydroxyhexanoic acid as described in PCT application publication no. WO-02/18369 as a compound xiii to which HBTU (455 mg, 1.2 mmol) and NMM (0.44 mL, 4 mmol) were added in acetonitrile and stirred at room temperature overnight. Saturated NH4Cl (10 mL) and ethyl acetate (10 mL) were added and, after 20 minutes, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over MgSO 4, filtered and filtered under reduced pressure to give 2-hydroxy-3 (S) - {3- (pyridin-3-ylmethanesulfonyl) -2 (R) '[2.2, 2-Trifluoro-1 ($) - (4-fluorophenyl) -ethylamino] propionylamino} hexanoic acid cyclopropylamide, which was used in the next step without further purification. Step 7 56 2-Chloro-3 (S) - {3- (pyridin-3-ylmethanesulfon) -2 (R) - [1,2,2-trifluoro-1 (5) - (4-fluorophenyl) ) -Ethylamino] propionylamino} hexanoic acid cyclopropylamide (590 mg, 1 mmol) in methylene chloride was slowly added to DMP. The reaction mixture was stirred at room temperature for 30 minutes and then added to 0.26 M Na2S2O3 saturated NaHCO3. The reaction mixture was stirred for 20 minutes. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over MgSO 4, filtered and concentrated to give 2-oxo-3 (S) - {3- (pyridin-3-ylmethanesulfonyl) -2 (R) - [2.2.2- trifluoro-1 (S) - (4-fluorophenylthiylamino) -propionylamino] -hexanoic acid cyclopropylamide purified on a flusholone (2% MeOH-CH2Cl2) to give the pure product as a yellow solid.

[0199] 1H-NMR(DMSOd6): δ 0.80 (m, 12H), 2.02(m, 1H), 3.3-3.7(b, 3H), 4.00(m, 1H), 4.46(m, 1H), 4.79(m, 2H), 7.25(m, 2H), 7.50(m, 2H), 7.65(b, 1H), 7.72(d, 1H), S.0l(d, IH), 8.71(m, 3H). LC-MS: 587(M+1), 585, (M-1), 609(M+23).1 H-NMR (DMSOd 6): δ 0.80 (m, 12H), 2.02 (m, 1H), 3.3-3.7 (b, 3H), 4.00 (m, 1H), 4.46 (m, 1H), 4.79 ( m, 2H), 7.25 (m, 2H), 7.50 (m, 2H), 7.65 (b, 1H), 7.72 (d, 1H), 4.01 (d, 1H), 8.71 (m, 3H). LC-MS: 587 (M + 1), 585, (M-1), 609 (M + 23).

[0200] Rīkojoties kā aprakstīts iepriekš, bet 3-pikolilhiorīdu aizvietojot ar ciklopropilmetilbromīdu, iegūst 2-okso-3(3)-{3-(ciklopropilmetānsulfonil)-2(/:?)-[2,2,2- trifluor-1(S)-(4-fluorfenil)etilamino]-propionilamino}heksānskābes ciklopropilamīdu (savienojums 1). 1H-NMR(DMSO-d6): δ 0.32-0.41 (m, 2H), 0.53-0.67 (m, 6H), 0.81 (t, J=7.2Hz, 3H), 1.06-1.38 (m, 4H), 1.52-1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, J=2.8Hz, J=14.8Hz, 1H), 3.19 (dd, J=8Hz, J=14Hz, 1H), 3.28-3,50 (m, 3H), 3.82-3.88 (m, 1H), 4.37 (kvinta, J=7.6Hz, 1H), 4.70-4.76 (m, 1H). 7.22 (t, J=8.4Hz, 2H), 7.43 (dd, J=5.-6Hz, J=8.4Hz, 2H), 8.51 (d, J=7.2Hz, 1H), 8.73 (d, J=5.2Hz, 1H). LC-MS: 550(M+1), 548, (M-1)· 2.piemērs 2-okso-3(S)-3-[2(/?)-(2,2,3,3,3-pentafluorpropilamino)-3-(piridil-3-ilmetānsulfonil)propionilamino]pentānskābes ciklopropilamīda sintēzeAs described above, and replacing 3-picolyl chloride with cyclopropylmethyl bromide, 2-oxo-3 (3) - {3- (cyclopropylmethanesulfonyl) -2 (t)-[2,2,2-trifluoro-1] is obtained. (S) - (4-Fluorophenyl) ethylamino] -propionylamino} hexanoic acid cyclopropylamide (Compound 1). 1 H-NMR (DMSO-d 6): δ 0.32-0.41 (m, 2H), 0.53-0.67 (m, 6H), 0.81 (t, J = 7.2Hz, 3H), 1.06-1.38 (m, 4H), 1.52 -1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, J = 2.8Hz, J = 14.8Hz, 1H), 3.19 (dd, J = 8Hz, J = 14Hz, 1H), 3.28 3.50 (m, 3H), 3.82-3.88 (m, 1H), 4.37 (quint, J = 7.6 Hz, 1H), 4.70-4.76 (m, 1H). 7.22 (t, J = 8.4Hz, 2H), 7.43 (dd, J = 5.6Hz, J = 8.4Hz, 2H), 8.51 (d, J = 7.2Hz, 1H), 8.73 (d, J = 5.2 Hz, 1H). LC-MS: 550 (M + 1), 548, (M-1) · Example 2 2-Oxo-3 (S) -3- [2 (t?) - (2,2,3,3,3) pentafluoropropylamino) -3- (pyridyl-3-ylmethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide synthesis

1.posms [0201] 2,2,3,3,3-pentafiuorpropān-1-ola (1.5 g, 10.0 mmol) šķīdumam metilēnhlorīda (75 mL), kura temperatūra sastādīja -78°C, un DIPEA (6.1 mL, 35.0 mmol) pievienoja (CF3S02)20 (1.78 mL, 10.5 mmol). Pēc 2.5 stundām pievienoja S-tritilcisteīnu vienā peņemienā un reakcijas maisījumu maisīja temperatūrā 0°C 80 minūšu laikā. Reakcijas maisījumu maisīja istabas temperatūrā 18 stundas un pēc tam koncentrēja rotovapā. Pievienoja etilacetātu un reakcijas maisījumu skaloja ar 1N HCI. Organisko kārtu žāvēja virs magnija sulfāta, filtrēja un koncentrēja. Jēlo. produktu attīrīja ar 57 57 LV 13669 flešhromatografiju (3 heksani/1 etilacetāts + 1% etiķskābes), iegūstot 2(R)-(2,2,3,3,3-pentafluorpropilamino)-3-tritilsulfanilpropānskābi (3.29 g). 2.posms [0202] 2(/?)-(2,2,3,3,3-pentafluorpropilamino)-3-triiilsulfanilpropānskābi (1.05 g, 2.12 mmol) šķīdumam metilēnhlorīdā (15 mL) pievienoja TFA (0.653 mL, 8.48 mmol), pēc tam trietilsilānu (0.677 mL, 4.24 mmol). Reakcijas maisījumu maisīja 1.5 stundu istabas temperatūrā un pēc tam koncentrēja rotovapā. Atlikumam pievienoja 2N NaOH šķīdumu (20 mL) un reakcijas maisījumu ekstrahēja ar heksānu. NaOH kārtai pievienoja tris(2-karboksitrietil)fosfma hidrohlorīdu (60 mg), pēc tam 3-pikolilhlorīda hidrohlorīdu (348 mg, 2.12 mmol). Pēc 1.5 stundas reakcijas maisījumu paskābināja arkonc. HCI līdz ~pH=4 un ekstrahēja ar etilacetātu. Organisko kārtu žāvēja un koncentrēja, iegūstot 2(f?)-(2,2,3,3,3-pentafluorpropilamino)-3-(piridin-3-ilmetānsulfonil)propānskābi (530 mg). 3. posms [0203] 2(R)-(2,2,3,3,3-pentafluorpropilamino)-3-(piridin-3-ilmetānsulfanil)propānskābi (151 mg, 0.44 mmol), 3(S)-amino-2-hidroksipentānskābes ciklopropilamīda hidrohlorīda (92 mg, 0.44 mmol), EDC (102 mg, 0.66 mmol) un HOBt hidrēta (71 mg, 0.53 mmol) šķīdumam pievienoja N-metilmorfolīnu (0.194 mL, 1.76 mmol). Reakcijas maisījumu maisīja 2 stundas un pēc tam atšķaidīja ar etilacetātu un skaloja ar nātrija bikarbonāta šķīdumu. Organisko kārtu koncentrēja, iegūstot 2-hidroksi- 3(S)-[2(/7)-(2,2,3,3,3-pentafluorpropilamino)-3-(piridin-3-ilmetānsuIfanil)propioni!amino]pentānskābes ciklopropilamīdu (170 mg). 4. posms [0204] 2-hidroksi- 3(S)-[2(R)-(2,2,3,3,3-peniafluorpropilamino)-3-(piridin-3-i!metānsulfanil)propioni!amino]penĪānskābes cikiopropilamīda (170 mg, 0.34 mmol) NMP šķīdumam pievienoja ΟΧΟΝΕ® (209 mg, 0.34 mmol) ūdens šķīdumu. Pēc 2 stundām vēlreiz pievienoja ΟΧΟΝΕ® (105 mg, 0.17 mmol)., papildinot ar ūdeni un nedaudz metanola. Vēl pēc 1 st. 40 min. reakcijas maisījumu atšķaidīja ar etilacetātu un mazgāja ar ūdeni. Organisko kārtu koncentrēja, iegūstot 2-hidroksi-3(S)-[2(R)-(2,2,3,3,3-pentafluorpropilamino)-3-(pindin-3-ilmetānsulfonil)propionilamino]pentānskābes ciklopropilamīdu (176 mg). 5.posms [0205] Heterogēnajam 2-hidroksi-3(S)-[2(R)-(2,2,3,3,3-pentafluorpropi!amino)-3-(piridin-3-ilmetānsulfonil)propionilamino]pentānskābes ciklopropilamīda (176 mg, 0.33 mmol) un metilēnhlorīdā maisījumam pievienoja Desa-Martina perjodinānu (183 mg, 0.43 mmol). Reakcijas maisījums kļuva heterogēns pēc dažām minūtēm. Pēc 3 stundām pievienoja acetonitrilu (3 mL), pēc tam NMP (6 mL), panākot homogēno reakciju. Šajā brīdī vēlreiz pievienoja Desa-Martina perjodinānu (100 mg). Maisīja vēl 70 minūtes, tad reakcijas maisījumu atšķaidīja ar etilacetātu un skaloja ar nātrija bikarbonāta šķīdumu. Organisko kārtu atdalīja un koncentrēja. Veicot atlikuma flešhromatogrāfiju (95% metilēnhlorīda/5% metanola), ieguva cietu vielu, ko suspendēja 1:1 IPA/etanola maisījumā un iztvaicēja līdz sausumam, iegūstot 2-okso-3(S)-3- 58 [2(/7)-(2,2,3,3,3-pentafluorpropi!am.ino}-3-(piridil-3-ilmeiānsulfonil)propionilamino]pentānskābes ciklopropilamīdu (87 mg). 3.piemers N-(1-ciklopropi!aminooksalilciklopropil)-3-cik!opropilmetansulfonil-2(Ej~[2,2,2-trifluor-1(S)-(4-fluorfeni!)eti!amino]propionamīda sintēzeStep 1: 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) for methylene chloride (75 mL) at -78 ° C and DIPEA (6.1 mL, 35.0). mmol) (CF 3 SO 2) 20 (1.78 mL, 10.5 mmol) was added. After 2.5 hours, S-tritylcysteine was added in one shot and the reaction mixture was stirred at 0 ° C for 80 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated on a rotovap. Ethyl acetate was added and the reaction mixture was washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated. I mean. The product was purified by 57 57 LV 13669 flush chromatography (3 hexane / 1 ethyl acetate + 1% acetic acid) to give 2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3-tritylsulfanylpropanoic acid (3.29 g). Step 2: 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3-triylsulfanylpropanoic acid (1.05 g, 2.12 mmol) in methylene chloride (15 mL) was added to TFA (0.653 mL, 8.48 mmol). ), followed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then concentrated on a rotovap. To the residue was added 2N NaOH solution (20 mL) and the reaction mixture was extracted with hexane. To the NaOH layer was added tris (2-carboxytriethyl) phosphorus hydrochloride (60 mg) followed by 3-picolyl chloride hydrochloride (348 mg, 2.12 mmol). After 1.5 hours the reaction was acidified with arconc. HCl to pH = 4 and extracted with ethyl acetate. The organic layer was dried and concentrated to give 2 (f) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propanoic acid (530 mg). Step 3: 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propanoic acid (151 mg, 0.44 mmol), 3 (S) -amino To a solution of 2-hydroxypentanoic acid cyclopropylamide hydrochloride (92 mg, 0.44 mmol), EDC (102 mg, 0.66 mmol) and HOBt (71 mg, 0.53 mmol) was added N-methylmorpholine (0.194 mL, 1.76 mmol). The reaction mixture was stirred for 2 hours and then diluted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer was concentrated to give cyclopropylamide of 2-hydroxy-3 (S) - [2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propionylamino] pentanoic acid. (170 mg). Step 4 2-Hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-peniafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionylamino] Cyclopropylamide of penic acid (170 mg, 0.34 mmol) was added to a solution of NMP (209 mg, 0.34 mmol) in water. After 2 hours, ΟΧΟΝΕ® (105 mg, 0.17 mmol) was added again with water and a little methanol. Another 1h 40 min. the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give cyclopropylamide of 2-hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pinnin-3-ylmethanesulfonyl) propionylamino] pentanoic acid (176 mg) ). Step 5 Heterogeneous 2-Hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide (176 mg, 0.33 mmol) and methylene chloride were added Desa-Martin periodin (183 mg, 0.43 mmol). The reaction mixture became heterogeneous in a few minutes. After 3 hours, acetonitrile (3 mL) was added followed by NMP (6 mL) to give a homogeneous reaction. At this point, Desa-Martin's periodin (100 mg) was added again. After stirring for another 70 minutes, the reaction mixture was diluted with ethyl acetate and rinsed with sodium bicarbonate solution. The organic layer was separated and concentrated. Purification by flash chromatography (95% methylene chloride / 5% methanol) gave a solid which was suspended in a 1: 1 IPA / ethanol mixture and evaporated to dryness to give 2-oxo-3 (S) -3- 58 [2 (/ 7)] - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridyl-3-ylethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide (87 mg) Example 3 N- (1-Cyclopropylaminocalylcyclopropyl) - Synthesis of 3-cyclopropylmethanesulfonyl-2 (Ej- [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] propionamide \ t

βθ2βθ2

1.posms [0206] 3-ciklopropilmetānsulfanil-2(R)-[2,2,2-irifluor-1(1S)-(4-fluorienil)etilamino]propānskābes (148 mg, 0.42mmol), ko pagatavoja kā aprakstīts iepriekš 1.piemērā, pikoliihlorīdu aizvietojot ar ciklopropilmetilbromīdu, un 2-(1-amino-cik!opropil)-N-ciklopropiI-2-hidroksiacetamīda (108 mg, 0.63 mmol) šķīdumam N- metiipirolidīnā (6 mL) temperatūrā 0°C pievienoja /V,/V-a'ietiipropi(amīnu (272 mg, 0.37 mL, 2.11 mmol) un HATU. Reakcijas maisījumu maisīja 4 stundas istabas temperatūrā. Reakcijas maisījumu atšķaidīja ar EtOAc un skaloja ar H2O. Organisko kārtu žāvēja (Na2S04) un koncentrēja, iegūstot N-[1-(dklopropilkarbamoilhidroksimetii)ciklopropil]-3-cikiopropilmetilsulfanil- 2-[2,2,2-trifiuor-1-(4-fluorrenil)-eti!amino]propionamīdu, ko pārvērta galvenajā savienojumā kā aprakstīts iepriekš 2.piemēra 4. un 5.posmā. MS (534.2 M+1, 532.1 M-1).Step 1: 3-Cyclopropylmethanesulfonyl-2 (R) - [2,2,2-irifluoro-1 (1S) - (4-fluorenyl) ethylamino] propanoic acid (148 mg, 0.42 mmol) prepared as described above In Example 1, substituting picolinyl chloride with cyclopropylmethyl bromide and 2- (1-amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetamide (108 mg, 0.63 mmol) in N-methylpyrrolidine (6 mL) was added at 0 ° C. V / N-Ethylpropi (amine (272 mg, 0.37 mL, 2.11 mmol) and HATU) The reaction mixture was stirred for 4 h at room temperature The reaction mixture was diluted with EtOAc and rinsed with H 2 O. The organic layer was dried (Na 2 SO 4) and concentrated. Obtaining N- [1- (dichloropropylcarbamoylhydroxymethyl) cyclopropyl] -3-cyclopropylmethylsulfanyl-2- [2,2,2-trifluoro-1- (4-fluorenyl) ethylamino] propionamide converted to the parent compound as described above 2. Example 4 and Step 5. MS (534.2 M + 1, 532.1 M-1).

[0207] Veicot 3.piemērā aprakstīto procedūru, bet 2-(1-amino-cīklopropil)-/\/-ciklopropil-2-hidroksiacetamīdu aizvietojot ar 3-amino-N-benzil-2-hidroksi-3-metilbutiramīdu, iegūst /V-benzil-3- {3-ciklopropilmeiānsulfonil-2(R)-[2,2,2-trifluor-1(S)-(4-fluorrenil)etilamino]propionilamino}-3-metil-2-okso-butiramīdu. · MS (586.3 M+1, 584.3 M-1).By performing the procedure described in Example 3, but replacing 2- (1-amino-cyclopropyl) - [(cyclopropyl-2-hydroxyacetamide) with 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide, V-Benzyl-3- {3-cyclopropylmethanesulfonyl-2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorenyl) ethylamino] propionylamino} -3-methyl-2-oxo-butyramide. · MS (586.3 M + 1, 584.3 M-1).

[0208] Veicot 3.piemērā aprakstīto procedūru, bet2-(1-amino-ciklopropi!)-/\/-cikIopropil-2-hidroksiacetamīdu aizvietojot ar 3-amino-/V-benzil-2-hidroksi-3-metilbutiramīdu un 2(R)-[2,2,2-trifiuoro-1(S)-(4-fluorfenil)etilamino]-3-tritilsulfanilpropānskābi ar 2(R)-[2,2,2-trifluor-1 (R)-(4-fluorfenil)etilamino]-3-tritilsulfanilpropānskābi, iegūst A/-benzil-3-{3-ciklopropilmetānulfonil-2(R)-[2,2,2- trifluor-1(/?)-(4-fluorfenil)etilamino]propionilamino}-3-metil-2-okso-butiramīdu. /V-benzil-3-{3-ciklopropilmetānsulfonīl-2-[2,2,2-trifluor-1-(4-fluorfenH)-eti!amino]- propionilamino}-3-metil-2-oksobutiramīda MS (586.1 M+1, 584.1 M-1).While performing the procedure described in Example 3, substituting 2- (1-amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetamide with 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide and 2 \ t (R) - [2,2,2-Trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid with 2 (R) - [2,2,2-trifluoro-1 (R) - ( 4-Fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid, obtained as N-benzyl-3- {3-cyclopropylmethanesulfonyl-2 (R) - [2,2,2-trifluoro-1 (1H) - (4-fluorophenyl) ethylamino ] propionylamino} -3-methyl-2-oxo-butyramide. N-Benzyl-3- {3-cyclopropylmethanesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -ethyl] -propionylamino} -3-methyl-2-oxobutyramide MS (586.1 M) +1, 584.1 M-1).

[0209] Veicot 3.piemērā aprakstīto procedūru, bet 2-(1-amino-ciklopropil)-AĪ-ciklopropii-2-hidroksiacetamīdu aizvietojot ar 3-amino-/\/-ciklopropil-2-hidroksi-3-metilbutiramīdu, ieguva 59 59 LV 13669 AAciklopropiK3^3-ciklopropilmetānsulfonil-2(/?)-[2,2,2- trifluor-1 (S)-(4-flūorfenil)etilamino]propionilamino}-3-metil-2-oksobutiramTdu. MS (536.0 M+1, 534.2 M-1). 4.piemērs 3 (S)-[3 -ciklopropilmetānsulfonil-2(R)-(2,2,3,3,3 -pentafluorpropilamino)-propionilaminoj-2-oksopentānskābes cikiopropilamīda sintēzeBy performing the procedure described in Example 3, but replacing 2- (1-amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetamide with 3-amino-cyclopropyl-2-hydroxy-3-methylbutyramide, 59 \ t 59 LV 13669 AAcyclopropyl 3,3-cyclopropylmethanesulfonyl-2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] propionylamino} -3-methyl-2-oxobutyramide. MS (536.0 M + 1, 534.2 M-1). Example 4 Synthesis of cyclopropylamide of 3 (S) - [3-cyclopropylmethanesulfonyl-2 (R) - (2,2,3,3,3-pentafluoropropylamino) -propionylamino] -2-oxopentanoic acid

1.posms [0210] 2,2,3,3,3-pentafluorpentān-1-ola (1.5 g, 10.0 mmol) un DIPEA(6.lmL, 35.0 mmol) šķīdumam dihlormetānā (75mL), kura temperatūra bija -78°C, pievienoja (triflic) (CFsSC^O (1.78 mL, 10.5 mmol) pilinot. Pēc 2 st. 20 min. reakcijas maisījumam pievienoja S-triiilcisteīnu un nepārtraukti maisīja 1 st. 15.min. 0°C un pēc tam 19 st. istabas temperatūrā. Reakcijas maisījumu koncentrēja rotovapā un atlikumu pakļāva flešhromatogrāfījai (3:1, heksāni/etilacetātsar 1% etiķskābi), iegūstot 2(/7)-(2,2,3,3,3-pentafluorpropilamino)-3-iritiIsuffanilpropānskābi (3.29g). 2.posms [0211] 2(/?)-(2,2,3,3,3-peniafluorpropi!amino)-3-tritilsulfanilpropānskābes (1.05 g, 2.12 mmol) šķīdumam dihlormetānā pievienoja TFA (0.653 mL, 8.48 mmol), pēc tam trietilsilānu (0.677 mL, 4.24 mmol). Reakcijas maisījumu maisīja 1 st. 20 min. istabas temperatūrā un pēc tam koncentrēja rotovapā. Atlikumam pievienoja 2N NaOH un heksānus. Maisījumu sakratīja un nodalīja NaOH kārtu. NaOH kārtai pievienoja ciklopropilmetilbromīdu (0.206 mL, 2.12 mmol). Reakcijas maisījumu maisīja 17 st. istabas temperatūrā un pēc tam paskābināja ar 1N HCI un produktu ekstrahēja ar etilacetātu. Etilacetāta kārtu skaloja ar sāls šķīdumu, žāvēja uz magnija sulfāta, filtrēja un koncentrēja, iegūstot 2(/?)-(2,2,3,3,3-pentafluorpropilamino)-3-ciklopropilmetānsulfanil) propānskābi (428 mg). 3.posms ' [0212] 2(R)-(2,2,3,3,3-pentafluorpropilamino)-3-(ciklopropilmetānsulfanil) propānskābes (150 mg, 0.49 mmol), 3(S)-amino-2-hidro.ksipentānskābes cikiopropilamīda hidrohlorīda (102 mg, 0.49 mmol), EDO (114 mg, 0.74 mmol) un HOBt (79 mg, 0.59 mmol) maisījumam dihlormetānā pievienoja N-metilmorfolīnu (0.215 mL, 1.96 mmol). Reakcijas maisījumu maisīja 2 stundas istabas temperatūrā un pēc tam atšķaidīja ar etilacetātu un skaloja ar nātrija bikarbonāta šķīdumu. Organisko kārtu žāvēja un koncentrēja, iegūstot 2-hidroksi-3(S)-[2(/7)-(2,2,3,3,3-pentaf!uorpropilamino)-3-(ciklopropilmetān sulfanil)propionilamino]pentānskābes ciklopropilamīdu (169' mg). 60 4.posms [0213] 2-hidroksi-3(S)-[2(R)-(2,2,3,3,3-pentafluorpropilamino)-3-(ciklopropilmetānsulfaniljpropioniļaminojpentānskābes ciklopropilamīda (169 mg, 0.37 mmol) šķīdumam NMP (5 mL) pievienoja ΟΧΟΝΕ (342 mg, 0.56 mmol) ūdens šķīdumu. Pēc samaisīšanas 2 stundas istabas temperatūrā vēlreiz pievienoja ΟΧΟΝΕ (228 mg) ūdens šķīdumu kopā ar metanolu (5 mL). Pēc papildu samaisīšanas 2 stundu laikā reakcijas maisījumu atšķaidīja ar etilacetātu un skaloja ar piesātināto sāls šķīdumu. Organisko kārtu atdalīja, žāvēja un koncentrēja, iegūstot baltu cietu vielu, kurai pievienoja dihlormeiānu (10 mL) un Desa-Martina perjodānu. Šim homogēnajam maisījumam pievienoja acetonitrilu (3 mL), pēc tam NMP (6 mL), kā rezultātā reakcijas maisījums kjuva homogēns. Pēc 5 stundām reakcijas maisījumu atšķaidīja ar etilacetātu un skaloja ar nātrija bikarbonāta šķīdumu. Organisko kārtu žāvēja un koncentrēja, iegūstot jēlo produktu baltas cietas vielas veidā. Šai baltajai vielai pievienoja etanolu un maisījumu uzsildīja, recirkulējot. Joprojām homogēno maisījumu atstāja atdzist līdz istabas temperatūrai un filtrēja, iegūstot galveno savienojumu baltas cietas vielas veidā (115 mg). M. pt 196.1-196.7°C.Step 1: 2,2,3,3,3-pentafluoropentan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6. 1 mL, 35.0 mmol) in dichloromethane (75 mL) at -78 ° C C, (triflic) (CFsSC4O (1.78 mL, 10.5 mmol) was added dropwise. After 2 h 20 min, the reaction mixture was treated with S-triilcysteine and stirred continuously for 1 h at 15 min at 0 ° C and then at 19 h. The reaction mixture was concentrated on a rotovap and the residue was subjected to flushchromatography (3: 1, hexane / ethyl acetate / 1% acetic acid) to give 2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3-iridylsulfanyl-propanoic acid ( Step 2: 2 (t) - (2,2,3,3,3-Pentafluoropropylamino) -3-tritylsulfanylpropanoic acid (1.05 g, 2.12 mmol) in dichloromethane was added to TFA (0.653 mL, 8.48 mmol), then triethylsilane (0.677 mL, 4.24 mmol) The reaction mixture was stirred for 1 h at room temperature for 20 min and then concentrated on a rotovap to which 2N NaOH and hexanes were added. Cyclopropylmethyl bromide (0.206 mL, 2.12 mmol) was added to the NaOH layer. The reaction mixture was stirred for 17 h. at room temperature and then acidified with 1N HCl and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3-cyclopropylmethanesulfonyl) propanoic acid (428 mg). Step 3 '2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3- (cyclopropylmethanesulfonyl) propanoic acid (150 mg, 0.49 mmol), 3 (S) -amino-2-hydroxy N-methylmorpholine (0.215 mL, 1.96 mmol) was added to a mixture of cyclopropylamide hydrochloride hydrochloride (102 mg, 0.49 mmol), EDO (114 mg, 0.74 mmol) and HOBt (79 mg, 0.59 mmol). The reaction mixture was stirred for 2 hours at room temperature and then diluted with ethyl acetate and rinsed with sodium bicarbonate solution. The organic layer was dried and concentrated to give cyclopropylamide of 2-hydroxy-3 (S) - [2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropylmethanesulfonyl) propionylamino] pentanoic acid ( 169 'mg). Step 4: [0213] 2-Hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropylmethanesulfonyl] propionylamino] -pentanoic acid for cyclopropylamide (169 mg, 0.37 mmol) for NMP (5 mL) was added ΟΧΟΝΕ (342 mg, 0.56 mmol) aqueous solution After stirring for 2 h at room temperature, ΟΧΟΝΕ (228 mg) aqueous solution was added again with methanol (5 mL) After stirring for 2 h, the reaction mixture was diluted with ethyl acetate. and washed with saturated brine, the organic layer was separated, dried and concentrated to give a white solid, to which was added dichloromethane (10 mL) and Desa-Martin periodan, to which was added acetonitrile (3 mL) followed by NMP (6 mL). After 5 hours, the reaction mixture was diluted with ethyl acetate and rinsed with sodium bicarbonate solution, the organic layer was dried and concentrated to give a crude product. White solid was added to this white substance and the mixture was heated to reflux. The homogeneous mixture was still left to cool to room temperature and filtered to give the title compound as a white solid (115 mg). M. pt 196.1-196.7 ° C.

[0214] Rīkojoties kā aprakstīts iepriekš, ieguva šādus savienojumus: N-ciklopropil-3S-{3-benzolsulfonil-2f?-[2,2,2-trifluor-1S-(4-fluorfenil)etilamino]propionilamino}-2-oksopentānamīdu, LC-MS 558(M+H) un ’ N-ciklopropil-3S-[3-ciklopropilmetānsulfonil-2R’-(2,2,3,3,4,4,4-heptafluorbutilamino)propionilamino]-2-oksopentānamīdu, LC-MS 542{M+H). 5.piemērs ' N-cikIopropil-3S-{4-metānsulfonil-2S-[2,2,2-irifluor-1 S-(4-fluorfeni!)etilamino]butirilamino}-2-oksopentānamīdasintēze [0215] (S) metil-2-amino-4-metilsulfanilbutirāta hidrohlorīdu (750 mg, 3.76 mmol) un 2,2,2-trif!uor-1-(4-fluorfeni!)etanonu (721 mg, 3.76mmo!) šķīdināja metanolā (15 mL) un šķīdumam pievienoja kālija karbonātu (1.04 g, 7.52 mmol). Maisījumu maisīja 55°C 23 stundas un pēc tam koncentrēja līdz sausam rotovapā. Atlikumu savienoja ar toluolu un maisījumu koncentrēja līdz sausam rotovapā. Atlikumu savienoja ar acetonitrilu (10 mL) un maisījumu maisīja temperatūrā aptuveni 30°C. Cinka borhidrīdu, ko pagatavoja, 1M cinka hlorīda šķīdumu ēterī (5.64 mL) pievienojot nātrija borhidrīda (427 mg, 11.28 mmol) maisījumam, samaisot ēteri (10 mL) un pēc tam šo maisījumu maisot 19 stundas, pievienoja reakcijas maisījumam, samaisot aptuveni 7 stundas pazeminātā temperatūrā un pēc tam vēl 16 stundas istabas temperatūrā. Reakcijas maisījumam pievienoja ar etilacetātu atšķaidīto 1N HCI un skaloja ar sāls šķīdumu (2X50mL).As described above, the following compounds were obtained: N-Cyclopropyl-3S- {3-benzenesulfonyl-2H- [2,2,2-trifluoro-1S- (4-fluorophenyl) ethylamino] propionylamino} -2-oxopentanamide , LC-MS 558 (M + H) and N-Cyclopropyl-3S- [3-cyclopropylmethanesulfonyl-2R '- (2,2,3,3,4,4,4-heptafluorobutylamino) propionylamino] -2-oxopentanamide, LC-MS 542 {M + H). Example 5 'N-Cyclopropyl-3S- {4-methanesulfonyl-2S- [2,2,2-irifluoro-1S- (4-fluorophenyl) ethylamino] butyrylamino} -2-oxopentanamide synthesis [0215] (S) Methyl -2-Amino-4-methylsulfanylbutyrate hydrochloride (750 mg, 3.76 mmol) and 2,2,2-trifluoro-1- (4-fluorophenyl) ethanone (721 mg, 3.76 mmol) were dissolved in methanol (15 mL) and potassium carbonate (1.04 g, 7.52 mmol) was added to the solution. The mixture was stirred at 55 ° C for 23 hours and then concentrated to dryness in a rotovap. The residue was combined with toluene and the mixture was concentrated to dryness on a rotovap. The residue was combined with acetonitrile (10 mL) and the mixture was stirred at about 30 ° C. Zinc borohydride prepared by adding 1M zinc chloride solution in ether (5.64 mL) to a mixture of sodium borohydride (427 mg, 11.28 mmol), stirring ether (10 mL) and then stirring for 19 h, was added to the reaction mixture with stirring for about 7 h. at a reduced temperature and then for a further 16 hours at room temperature. 1N HCl diluted with ethyl acetate was added to the reaction mixture and washed with brine (2X50mL).

Organisko kārtu žāvēja un koncentrēja, iegūstot 2S-[2,2,2-trifluor-IS-(4-fluorfenil)etilamino]-4-metiisulfanilsvīestskābi (1.15 g) cietas vielas veidā.The organic layer was dried and concentrated to give 2S- [2,2,2-trifluoro-IS- (4-fluorophenyl) ethylamino] -4-methylsulfanyl-uric acid (1.15 g) as a solid.

[0216] 2S-[2,2,2-trifluor-1S-(4-fluorfenil)etilamino]-4-metilsulfani!sviestskābi (150 mg, 0.46 mmol), ciklopropīl-3S-amino-2-hidroksipentānamīda hidrohlorīdu (106 mg, 0.51 mmol), EDC (132 mg, 0.69 mmol) un HOBt (75 mg, 0.55 mmol) savienoja DCM (10 mL) un šo maisījumu maisīja istabas 61 61 LV 13669 temperatūrā, pa šo laiku pievienojot N-metiimorfolīnu (0.253 mL, 2.3 mmol). Maisījumu maisīja 2 stundas 15 minūtes un pēc tam atšķaidīja ar etilacetātu. Maisījumu skaloja ar nātrija bikarbonāta šķīdumu (2X35mL) un organisko kārtu žāvēja un koncentrēja, iegūstot N-ciklopropi!-2-hidroksi-3S- {4-metānsulfonil-2S-[2,2,2-trifluor:1S-(4-fluorfenil)etilamino]buiirilamino} pentānamīdu (188 mg) baltas cietas vielas veidā.2S- [2,2,2-Trifluoro-1S- (4-fluorophenyl) ethylamino] -4-methylsulfanedioic acid (150 mg, 0.46 mmol), cyclopropyl-3S-amino-2-hydroxypentanamide hydrochloride (106 mg) , 0.51 mmol), EDC (132 mg, 0.69 mmol) and HOBt (75 mg, 0.55 mmol) were combined with DCM (10 mL) and the mixture was stirred at room 61 61 LV 13669, while N-methylmorpholine (0.253 mL, m.p. 2.3 mmol). The mixture was stirred for 2 hours 15 minutes and then diluted with ethyl acetate. The mixture was washed with sodium bicarbonate solution (2X35mL) and the organic layer dried and concentrated to give N-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2S- [2,2,2-trifluoro: 1S- (4-fluorophenyl) ) ethylamino] butyrylamino} pentanamide (188 mg) as a white solid.

[0217] A/-ciklopropil-2-hidroksi-3S-{4- metānsuIfoni!-2S-[2,2,2-trifluor-1 S-(4-fluorfenil)etilamino]butiri[amino}pentānamīdu (188mg, 0.39mmol).šķīdināja 1-metil-2-pirolidinonā (5 mL) un šķīdumu maisīja istabas temperatūrā, pa šo laiku pievienojot oksona ūdens šķīdumu (5 mL, 434 mg, 0.71 mmol). Maisījumu maisīja 1 st. 45 min. un pēc tam atšķaidīja ar etilacetātu. Maisījumu skaloja ar sālsūdeni (3x25mL) un organisko kārtu žāvēja un koncentrēja. Atlikumu šķīdināja 1-meti!-2-pirolidinonā (5 mL) un šķīdumam pievienoja Desa-Martina perjodānu (232 mg, 0.55 mmol). Reakcijai ļāva risināties 1 stundu un pēc tam šķīdumu atšķaidīja ar etilacetātu. Maisījumu mazgāja ar nātrija bikarbonāta šķīdumu (3x30mL) un organisko kārtu žāvēja un koncentrēja. Atlikumu savienoja ar ēteri un pievienoja cietai vielai. Maisījumu noskrāpēja un nofiltrēja, iegūstot A/-ciklopropil-3S-{4-metānsulfonil- 2S-[2,2,2-trifluoro-1S-(4-fluorfenil)etilamino]-butirilamino}-2-oksopentānamīdu (114 mg) baltas cietas vielas veidā (mp 152.5-153.5°C). LC-MS 510(M+H).N-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2S- [2,2,2-trifluoro-1 S- (4-fluorophenyl) ethylamino] butyr [amino] pentanamide (188 mg, 0.39) mmol) was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and the solution was stirred at room temperature while the oxone aqueous solution (5 mL, 434 mg, 0.71 mmol) was added. The mixture was stirred for 1 h. 45 min. and then diluted with ethyl acetate. The mixture was washed with brine (3x25mL) and the organic layer was dried and concentrated. The residue was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and Desa-Martina Periodane (232 mg, 0.55 mmol) was added to the solution. The reaction was allowed to proceed for 1 hour and then diluted with ethyl acetate. The mixture was washed with sodium bicarbonate solution (3x30mL) and the organic layer was dried and concentrated. The residue was combined with ether and added to a solid. Scrape off and filter the mixtures to give N-cyclopropyl-3S- {4-methanesulfonyl-2S- [2,2,2-trifluoro-1S- (4-fluorophenyl) ethylamino] -butyrylamino} -2-oxopentanamide (114 mg) white as a solid (mp 152.5-153.5 ° C). LC-MS 510 (M + H).

Bioloģiskie piemēri 1.piemērs Katepsīna B tests [0218] Testējamo savienojumu dažādu koncentrāciju šķīdumus pagatavoja 10 pL dimetilsulfoksīda (DMSO) un pēc tam atšķaidīja, iegūstot testa buferi (40 pL, kas saturēja N,N-bis(2-hidroksietil)-2-aminoetānsu)foskābi (BES), 50 mM (pH 6); polioksietilēnsorbitānmonolaurātu, 0.05%; un ditiotreitolu (DTT), 2:5 mM). Atšķaidītajiem maisījumiem pievienoja cilvēka katepsīnu B (0.025 pMol 25 pL testa bufera). Testa šķīdumus maisīja 5-10 sekundes uz šeikera šķīvīša, aiztaisīja ar vāciņiem un turēja 30 minūtes istabas temperatūrā. Z-FR-AMC (20 nMol 25 pL testa buferis) pievienoja testa šķīdumiem un hidrolizēs gaitu novēroja ar spektrofotometru (λ 460 nm) 5 minūtes. Šķietamās inhībēšanas konstantes (Kj) aprēķināja pēc enzimatiskā procesa līknēm ar standarta matemātikas metodēm.Biological Examples Example 1 Cathepsin B Test Various concentrations of test compound solutions were prepared in 10 µL dimethylsulfoxide (DMSO) and then diluted to give test buffer (40 µL containing N, N-bis (2-hydroxyethyl) -2- aminoethane) phosphoric acid (BES), 50 mM (pH 6); polyoxyethylene sorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2: 5 mM). Human cathepsin B (0.025 pMol 25 pL test buffer) was added to the diluted mixtures. The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-FR-AMC (20 nMol 25 pL test buffer) was added to test solutions and hydrolysed the course with a spectrophotometer (λ 460 nm) for 5 minutes. Apparent inhalation constants (Kj) were calculated by enzymatic curves with standard mathematical methods.

[0219] Izgudrojumā aprakstītos savienojumus testēja saskaņā ar iepriekš minēto testu un konstatēja, ka šie savienojumi inhibē katepsīna B aktivitāti. 2.piemērs Katepsīna K tests [0220] Testējamo savienojumu dažādu koncentrāciju šķīdumus pagatavoja 10 pL dimetilsulfoksīda (DMSO) un pēc tam atšķaidīja, iegūstot testa buferi (40 pL, kas saturēja MES, 5.0 mM (pH 5.5); EDTA, 2.5 mM; un DTT, 2.5 mM). Atšķaidītajiem maisījumiem pievienoja cilvēka katepsīnu K (0.0906 pMol 25 pL testa bufera)! Testa šķīdumus maisīja 5-10 sekundes uz šeikera šķīvīša, aiztaisīja ar vāciņiem un turēja 30 minūtes istabas temperatūrā. Z-Phe-Arg-AMC (4 nMol 25 pL testa buferis) pievienoja testa šķīdumiem un hidrolīzes 62 gaitu novēroja ar spektrofotometru. (λ 460 nm) 5 minūtes. Šķietamās inhibēšanas konstantes (Kj) aprēķināja pēc enzīmatiskā procesa līknēm ar standarta matemātikas metodēm.The compounds described in the invention were tested according to the above test and found to inhibit cathepsin B activity. EXAMPLE 2 Cathepsin K Assay [0220] Solutions of various concentrations of test compounds were prepared in 10 µL of dimethylsulfoxide (DMSO) and then diluted to give a test buffer (40 pL containing MES, 5.0 mM (pH 5.5); EDTA, 2.5 mM; DTT, 2.5 mM). Human cathepsin K (0.0906 pMol 25 pL test buffer) was added to the diluted mixtures! The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Phe-Arg-AMC (4 nMol 25 pL assay buffer) was added to the test solutions and hydrolysis 62 was observed with a spectrophotometer. (λ 460 nm) 5 minutes. The apparent inhibitory constants (Kj) were calculated from the curves of the enzymatic process with standard mathematical methods.

[0221] Izgudrojumā aprakstītos savienojumus testēja saskaņā ar iepriekš minēto testu un konstatēja, ka šie savienojumi inhibē katepsīna K aktivitāti. 3.piemērs Katepsīna L tests [0222] Testējamo savienojumu dažādu koncentrāciju šķīdumus pagatavoja 10 pL dimetilsulfoksīda (DMSO) un pēc tam atšķaidīja, iegūstot testa buferi (40 pL, kas saturēja MES, 50 m'M (pH 5.5); EDTA, 2.5 mM; un DTT, 2.5 mM). Atšķaidītajiem maisījumiem pievienoja cilvēka katepsīnu L (0.05 pMol 25 pL testa bufera). Testa šķīdumus maisīja 5-10 sekundes uz šeikera šķīvīša, aiztaisīja ar vāciņiem un turēja 30 minūtes istabas temperatūrā. Z-Phe-Arg-AMC (1 nMol 25 p L testa buferis) pievienoja testa šķīdumiem un hidrolizēs gaitu novēroja ar spektrofotometru (λ 460 nm) 5 minūtes. Šķietamās inhibēšanas konstantes (Kj) aprēķināja pēc enzīmatiskā procesa līknēm ar standarta matemātikas metodēm.The compounds described in the invention were tested according to the above test and found to inhibit the activity of cathepsin K. Example 3 Cathepsin L Assay Various concentrations of test compound solutions were prepared in 10 µL dimethylsulfoxide (DMSO) and then diluted to give test buffer (40 pL containing MES, 50 m'M (pH 5.5); EDTA, 2.5 mM) ; and DTT, 2.5 mM). Human cathepsin L (0.05 pMol 25 pL assay buffer) was added to the diluted mixtures. The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Phe-Arg-AMC (1 nMol 25 p L test buffer) was added to the test solutions and hydrolysed the course with a spectrophotometer (λ 460 nm) for 5 minutes. The apparent inhibitory constants (Kj) were calculated from the curves of the enzymatic process with standard mathematical methods.

[0223] Izgudrojumā aprakstītos savienojumus testēja saskaņā ar iepriekš minēto testu un konstatēja, ka šie savienojumi inhibē katepsīna L aktivitāti. 4.piemērs Katepsīna S tests [0224] Testējamo savienojumu dažādu koncentrāciju šķīdumus pagatavoja 10 μ!_ dimetilsulfoksīda (DMSO) un pēciam atšķaidīja, iegūstot testa buferi (40 μ!_, kas saturēja MES, 50 mM (pH 6.5); EDTA, 2.5 mM; un NaCI, 100 mM); β-merkaptoetanolu, 2.5 mM; un BSA, 0.00%. Atšķaidītajiem maisījumiem pievienoja cilvēka katepsīnu O (0.05 pMol 25 pL testa bufera). Testa šķīdumus maisīja 5-10 sekundes uz šeikera šķīvīša, aiztaisīja ar vāciņiem un turēja 30 minūtes istabas temperatūrā. Z-Val-Val-Arg-AMC (4 nMol 25 pL testa buferis, kas saturēja 10% DMSO) pievienoja testa šķīdumiem un hidrolizēs gaitu novēroja ar spektrofotometru (λ 460 nm) 5 minūtes. Šķietamās inhibēšanas konstantes (Kj) aprēķināja pēc enzīmatiskā procesa līknēm ar standarta matemātikas metodēm.The compounds described in the invention were tested according to the above test and found to inhibit the activity of cathepsin L. Example 4 Cathepsin S Assay Various concentrations of test compound solutions were prepared in 10 µl of dimethylsulfoxide (DMSO) and subsequently diluted to give a test buffer (40 µl containing MES, 50 mM (pH 6.5); EDTA, 2.5). mM; and NaCl, 100 mM); β-mercaptoethanol, 2.5 mM; and BSA, 0.00%. Human cathepsin O (0.05 pMol 25 pL test buffer) was added to the diluted mixtures. The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Val-Val-Arg-AMC (4 nMol 25 pL test buffer containing 10% DMSO) was added to the test solutions and hydrolysed the course with a spectrophotometer (λ 460 nm) for 5 minutes. The apparent inhibitory constants (Kj) were calculated from the curves of the enzymatic process with standard mathematical methods.

[0225] Izgudrojumā aprakstītos savienojumus testēja saskaņā ar iepriekš minēto testu un konstatēja, ka šo savienojumu katepsīna S inhibēšanas aktivitāte vienāda vai mazāka kā 100 nm. 5. piemērs Katepsīna F tests [0226] Testējamo savienojumu dažādu koncentrāciju šķīdumus pagatavoja 10 pL dimetilsulfoksīda (DMSO) un pēc tam atšķaidīja, iegūstot testa buferi (40 pL, kas saturēja MES, 50 mM (pH 6.5); EDTA, 2.5 mM; un NaCI, 100 mM); DTT, 2.5 mM; un BSA, 0.01%.Atšķaidītajiem maisījumiem pievienoja'cilvēka katepsīnu F (0.1 pMol 25 pL testa bufera). Testa šķīdumus maisīja 5-10 sekundes uz šeikera šķīvīša, aiztaisīja ar vāciņiem un turēja 30 minūtes istabas temperatūrā. Z-Phe-Arg-AMC (2 nMol 25 pL testa bufera, kas saturēja 63 LV 13669 10% DMSO) pievienoja testa šķīdumiem un hidrolizēs gaitu novēroja ar spektrofotometru (λ 460 nm) 5 minūtes. Šķietamās inhibēšanas konstantes (Kj) aprēķināja pēc enzimatiskā procesa līknēm ar standarta matemātikas metodēm [0227] izgudrojuma aprakstītos savienojumus testēja saskaņā ar iepriekš minēto testu un konstatēja, ka šie savienojumi inhibē katepsīna F aktivitāti. 1.piemērs[0225] The compounds described in the invention were tested according to the above test and found to have a cathepsin S inhibitory activity of less than or equal to 100 nm. Example 5 Cathepsin F assay [0226] Solutions of various concentrations of test compounds were prepared in 10 pL dimethylsulfoxide (DMSO) and then diluted to give test buffer (40 pL containing MES, 50 mM (pH 6.5); EDTA, 2.5 mM; NaCl, 100 mM); DTT, 2.5 mM; and BSA, 0.01% .The diluted mixtures were added 'human cathepsin F (0.1 pMol 25 pL assay buffer). The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Phe-Arg-AMC (2 nMol 25 pL assay buffer containing 63 U of 13669 10% DMSO) was added to test solutions and hydrolysed by spectrophotometer (λ 460 nm) for 5 minutes. The apparent inhibitory constants (Kj) were calculated by enzymatic process curves with standard mathematical methods. The compounds described in the invention were tested according to the above test and found to inhibit cathepsin F activity. Example 1

Raksturīgākie farmaceitiski sastāvi, kas satur savienojumu ar formulu (I)Typical pharmaceutical compositions containing a compound of formula (I)

PERORĀLAi LIETOŠANA! 10-100 mg 105 mg 18 mg papildinot līdz 100 mLORAL USE! 10-100 mg 105 mg 18 mg supplemented to 100 mL

SASTĀVSTHE COMPOSITION

Savienojums ar formulu (I) Citronskābes monohidrāts Nātrija hidroksīds Piedevas garšas uzlabošanai ŪdensCompound of formula (I) Citric acid monohydrate Sodium hydroxide Additive flavor enhancement Water

SASTĀVS INTRAVENOZAI LIETOŠANAICOMPOSITION FOR INTRAVENOUS USE

Savienojums ar formulu (I) Dekstrozes monohidrāts Citronskābes monohidrāts Nātrija hidroksīds Ūdens injekcijai 0.1-10 mg daudzums, kas pietiekams izotoniskā sastāva pagatavošanai 1.05 mg 0.18 mgCompound of Formula (I) Dextrose Monohydrate Citric Acid Monohydrate Sodium Hydroxide Water Injection 0.1-10 mg Sufficient For Isotonic Formulation 1.05 mg 0.18 mg

daudzums, kas pietiekams 1.0 mLsufficient 1.0 mL

SASTĀVS TABLETĒMCONTAINS TABLETS

Savienojums ar formulu (I) ' 1%Compound of formula (I) '1%

Mikrokristāliskā celuloze 73%Microcrystalline cellulose 73%

Stearskābe 25%Stearic acid 25%

Koloīdals silīcija dioksīds 1 % [0228] Šis izgudrojums krietni daudz detaļās tika aprakstīts, ilustrējot un minot piemērus skaidrības un saprašanas nolūkā. Personai, kurai ir kvalifikācija šajā jomā, būs acīmredzams, ka praksē iespējamas izmaiņas un modifikācijas pievienoto pretenziju ietvaros. Tātad, jāsaprot, ka iepriekš minētajam aprakstam ir ilustratīvs, nevis ierobežojošs raksturs. Tātad, izgudrojuma saturs jānosaka nevis pēc izgudrojuma apraksta, bet pēc šeit pievienotajām pretenzijām kopā ar visiem ekvivalentiem, uz kuriem Šīs pretenzijas dod tiesības. 1 1LV 13669Silicon Dioxide 1% [0228] This invention has been described in much detail, illustrating and illustrating examples for the sake of clarity and understanding. A person with a qualification in this field will obviously be able to make changes and modifications in practice within the attached claims. Thus, it should be understood that the above description is illustrative and not restrictive. Thus, the contents of the invention should be determined not by the description of the invention but by the claims appended hereto, together with all equivalents to which these claims give rise. 1 1LV 13669

ALPHA KETOAMEDE COMPOUNDS AS CYSTEINE PROTEASĒ DVHIBITORS CROSS-REĪERENCES TO RELATED APPLICATIONS [0003] ' This application oļains the benefit ofprovisional Patent Application No. 60/663,910, filed March 21,2005 and Provisional Patent Application No. 60/684,623, filed May 24, 2005, both of which aie incoīpoiated berein by reference.ALPHA KETOAMEDE COMPOUNDS AS CYSTEINE PROTEAS DVHIBITOR CROSS-REFERENCES TO RELATED APPLICATIONS [0003] 60 / 663,910 filed March 21,2005 and Provisional Patent Application No. 60 / 684,623 filed May 24, 2005, both of which are incoïpoiated berein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDER4LLY SPONSOSED RESEARCH OR DEVELOPMENTSTATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDER4LLY SPONSOSED RESEARCH OR DEVELOPMENT

[0002] NOT APPLICABLENOT APPLICABLE

REFERENCE TO A &quot;SEQUENCE LISTING,” ATABLE, OR A COMPUTER PROGRAM LISTING APPENDK SUBM2TTED ΟΝ A COMPACT DISKREFERENCE TO A "SEQUENCE LISTING," ATABLE, OR A COMPUTER PROGRAM LISTING APPENDK SUBM2TTED ΟΝ A COMPACT DISK

[0003] NOT APPLICABLENOT APPLICABLE

MELE» OF THE INVENTIONMELE »OF THE INVENTION

[0094] ' Tbe present invention is directed to compounds tbat are inhibitors of cysteine proteases, inparticular, catbepsins B, K, L, F, and S and are tberefore usefiil in treating diseases mediaied by these proteases. The present invention is also directed to phannaceutical compositions comprising these compounds andprocssses for prepaiing thein.[0094] 'Tbe present invention is directed to inhibitors of cysteine proteases, inparticular, catbepsins B, K, L, F, and S and are tberefore usefilter in these diseases. These compounds andprocssses for prepaiing thein.

STATE OF THE ARTSTATE OF THE ART

[0005] Cvsteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteīne proteases are associated with the nonnal degradation and processing of proteīns, The abeirant activity of cysteine proteases, e.g., as a result of increased expression or enhanced activation, however, mayhave pathological consequences. In this regard, certain cysteine proteases are associated witb a number of disease States, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B Ievels and redistribution of the enzyme are found in tumors; thus, suggestmg a role for the enzyme in tmnor invasion and metastasis. In 2 addition, aberrant cathepsin B activiiyis implicated in such disease states as rheumatoid arthritis, osteoarthritis, pneumocystis caiinii, acute pancreatitis, inflammatory airway disease and bone and joint disoīders.[0005] Cvsteine proteases represent a class of peptidases. Cysteine proteases are associated with the abnormal degradation and processing of protein, eg, mayhave pathological consequences. Cysteine proteases are associated witb a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B Ievels and redistribution of the enzyme are found in tumors; thus, a role for the enzyme in tmnor invasion and metastasis. In 2 additions, aberrant cathepsin implants in rheumatoid arthritis, osteoarthritis, pneumocystis caiinii, acute pancreatitis, inflammatory airway disease and bone and joint disorder.

[0006] The prominent expression of cathepsin K in osteoclasis and osteoclast-related multinucleated celis and iis high collagenolytic activity suggest fhat the enzyme is involved in osteoclast-mediated bone resoīption and, hence, in bone abnonnalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and iis elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.The prominent expression of cathepsin in osteoclast and osteoclast-related multinucleated celis and iis high collagenolytic activity suggestion of osteoclast-mediated bone resorption and hence in osteoporosis. In addition, cathepsin K expression in the lung and iis elastinolytic activity suggest that a role in pulmonary disorders as well.

[0007] Cathepsin L is implicated in normai lysosomal proteolysis as well as in several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and cērtam autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Gravēs' disease, myasthenia grayis, systemic lupus erythemotasus, rheumatoid arthritis, neuroņathic pain, and Hashimoto's thyroiditis. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to asthma; 'and allogeneic immune reponses, including, but not limited to, rejecrion of organ transnlants or tissue grafts.Cathepsin L is implicated in norms for lysosomal proteolysis as well as in several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's Disease and Cramam Autoimmune Disorders, including Multiple Sclerosis, Pemphigus Vulgaris, Graves' Disease, Myasthenia Grayis, Systemic Lupus Erythematosus, Rheumatoid Arthritis, Neuronathic Pain, and Hashimoto's Thyroiditis. In addition, cathepsin is implicated in: allergic disorders, including but not limited to asthma; and allogeneic immune reponses, including but not limited to, rejecrion of organ transnlants or tissue grafts.

[0008] in view of the number of diseases wherein it is recognized that an increase in cysteine proiease activity contributes to the pathology and/or symptomatology of the disease, molecules which inhibit the actrvity of this class of enzymes, in particular molecules which inhibit cathepsins B, K, L, F, and/or S, will iherefore be useful as therapeutic aģents.Which inhibit cathepsins, in particular molecules which inhibit cathepsins, and inhibit cathepsins. B, K, L, F, and / or S will iherefore be useful as therapeutic agent.

SUMMARY OF THE INVENTIONSUMMARY OF THE INVENTION

[0009] In one aspect, this invention is directed to a compound of Formula (I):In one aspect, a compound of Formula (I):

RR

R8 H where: R1 is hydrogen or alkyl; R2 is cycloalkyl, cycloaIky3aIkyi, araBcyī, heteroaryl, orheteroaralkyl optionally substituted with one or two substitutents inaependently selected from alkyl, a!koxy, orhalo; R3 is hydrogen, alkyl or alkoxyalkyl; 3 3LV13669 R4 is aBcyl; or R3 and R4 togeiher with the carbon atom to which they are attached forta cycloalkylene optionally substitated v/ith one to four iluoro or heterocycloal!cylene optionally substituted with alkyl, alkoxyaIkyl, hydroxyaIky3, acyl, cycloalkyl, cycloaIkylalkyl, or iialoalkyl; R5 is aūcyl, haloaIkyl optionally substituted wiih cycloalkyl, aiyl, beteroaiyl, or heterocycloaīky3, cycloalkylalkyl3 aralkyl, heteroaraIkyl, heterocycloalkylaīkyl, -(alkylene)-X-R9 (where X is -0-, S-, -SO-, -S02-, -CONH-, -NHCO-, or -NHS02- and R9 is albyl, haloaIkyl, cycloalkyl, cycIoa!kylaIkyli aryl, aralkyl, beteroaryl; heteroaralkyl, heterocycloaIkyl, or heterocydoaIkylalkyl), or -(a^Ienej^-thaloalfr/lenej-R10 (whereX' is -0-, -S-, -SO-, -S02-, -CONH-, -NHCO-, or -NHS02- and R10 is cyoloa]kyl, aryl, heteroaryl, or heierocycIoaJkyl), wherein the aromatic or alicyclic ring in R5is optiona]ly substituted with one, two, or three Ra independently selected from alkyi, haloaIkyl, a]i;oxy, hydroxy, haIoalk:oxy, cyano, balo, carboxy, or alkoxycarbcnyl; or optionalIy substituted with one or two Rb independenilv seieeted nrom hydrogen, a3kyl, haloalkyĻ alkoxy, hydroxy, haloalkoxyj balo, caxboxy, or aīkoxycarbonyl and oneRc selected from hydroxya!kyī, alioxya!kyi, anainoallcy!, siyl, heteroaiyl, aralkyl, heteroarall&lt;yl, cycloaUryl, cycloalicyla3kyl, heterocycloalkyl, heterocyc3oalkylalkyl, acyl, acylalkyl. aiyloxycarbonyl, aralky3oxycarbonyl, beieroaiyloxycarbonyl, heieroaralkyloxycarboūyl, heierocyxloalkyloxycarbonyi, cycloa!kyloxycarbonyl, aryloxy, heteroaryloxy, ara!kyloxy, heieroaral]cyloxy, aminocarbonyl, armriosulfonyl, or -SO2R11 (vriiere R11 is alkyl, cycloalkyl, aryl, heteroaiyl, or heierocycloaIkyļ); and further wherein the aromatic or alicyclic ring in Rc is opiionally substituted -with one, two, or three Rd independently selected from alkyl, a3kylsulfonyl, baloalkyl, atkoxy, bydroxy, haloalkoxy, or balo; R6 is haloalkyl; R7 is hydrogen, alķyl, 01 haloalkyl; and R8 is bydxogen, allcyl, haloalkyl, cycloalkyl, aryl, beteroaryl, heterocycloalkyl attached via a carbon atom wherein the aromatic or alicycbc ring in R is optionally substituted with one, tvo, or three Reindependently selected from altyl, balo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, allcoxycarbonyl, carboxy, cyano, alkylsulfonyl, a]kylsutfonylarmnoi aminocarbonyl, or aminosulfonyl; or a phannaceuticaUy acceptable salts thereof 4 [0010] In a second aspect, fhis invention is directed to a pharmaceutical composition comprising a compound of Fommia (I) or apharmaceutically acceptable sali thereof in admixture with one or more suitable excipients.R8 is H: R1 is hydrogen or alkyl; R2 is cycloalkyl, cycloaIky3aIkyi, araBcy, heteroaryl, orheteroaralkyl substituted with one or two substituents inaependently selected from alkyl, a! Koxy, orhalo; R3 is hydrogen, alkyl or alkoxyalkyl; 3 3LV13669 R4 is aBcyl; or R 3 and R 4 togeiher with the carbon atom to which they are attached for cycloalkylene optionally substituted with alkyl, alkoxy, alkyl, hydroxyl, acyl, cycloalkyl, cycloalkyl, oralkylalkyl; R5 is acyl, haloalkyl substituted substituted cycloalkyl, allyl, beterooyl, or heterocycloalkyl3, cycloalkylalkyl3 aralkyl, heteroarylalkyl, heterocycloalkylalkyl, - (alkylene) -X-R9 (where X is -O-, S-, -SO-, -SO2- , -CONH-, -NHCO-, or -NHSO 2 - and R 9 is albyl, haloalkyl, cycloalkyl, cycloalkoxyalkyl aryl, aralkyl, beteroaryl; heteroaralkyl, heterocycloalkyl, or heterocydoalkylalkyl), or - (a ^ Ien-thaloalph / lenej) -R10 (whereX 'is -O-, -S-, -SO-, -SO2-, -CONH-, -NHCO-, or -NHSO2- and R10 is cyloo] yl, aryl, heteroaryl, or heierocycloJkyl), selected from one, two, or three Ra or selected from alky, haloIkyl, a] i; oxy, hydroxy, halo: oxy, cyano, balo, carboxy, or alkoxycarbcnyl; or optionalIy substituted with one or two Rb independenilv seieeted nrom hydrogen, a3kyl, haloalkylo alkoxy, hydroxy, haloalkoxyj balo, caxboxy, or aikoxycarbonyl and oneRc selected from hydroxya! kyī, alioxya! kyi, anainoallcy !, siyl, heteroaryl, aralkyl, heteroaryl &lt; yl, cycloaUryl, cycloalicyl3yl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl. aiyloxycarbonyl, aralky3oxycarbonyl, beieroaiyloxycarbonyl, heieroaralkyloxycarboūyl, heierocyxloalkyloxycarbonyi, cycloalkyl! kyloxycarbonyl, aryloxy, heteroaryloxy, ara! kyloxy, heieroaral] cyloxy, aminocarbonyl, armriosulfonyl, or -SO2R11 (vriiere R11 is alkyl, cycloalkyl, aryl, heteroaiyl, or heierocycloaIkyļ); and furthermore, selected from alkyl, a3, sulfonyl, baloalkyl, atxyxy, bydroxy, haloalkoxy, or balo; R6 is haloalkyl; R 7 is hydrogen, alkyl, 01 haloalkyl; and R8 is bydxogen, allcyl, haloalkyl, cycloalkyl, aryl, beteroaryl, heterocycloalkyl attached via carbon atoms, aromatic or alicyclc ring in R is optionally substituted with one, tvo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, allcoxycarbonyl, carboxy, cyano, alkylsulfonyl, a] cyclopropylamino or aminocarbonyl, or aminosulfonyl; or a phannaceuticaUy acceptable salts of a compound of the invention. A compound of the invention is a compound of the invention.

[0011] In a third aspect, this invention is diiected to a method for treating a disease in an animal mediated by cysteine proteases, in particular cathepsin S, which method comprises administering to the animal aphannaceutical composition comprising a therapeutically effective amount of a compound of Formula (T) or a pharmaceutically acceptable salt thereof in admiīture \vith one or more suitable excipients.A method of treating an animal with a cysteine protease, which is a method of treating an animal. One or more suitable excipients for the formula (T).

[0012] In a fourth aspect, this invention is directed to processes for preparing compounds of Formula (Γ).[0012] In a fourth aspect, this invention is directed to processes for preparing compounds of Formula (Γ).

[0013] In a nfth aspect, this invention is directed to a method of treating a palieni undergoing a therapy wherein the therapy causes an immune response, preferably a deleterious immune response, in the patient comprising adininistering to the patient a compound of Formula (I) or aphannacsuiica31y acceptable salt thereof. Preferably, the immune response is mediated by MHC class Π molecules. The compound of this invention. can be admirdstered prior to, simultaneonsly. or after the therapy. Preferablv, the therapy iovolves treatment with a biologic. Preferably, the therapy involves treatment v/iih a small molecule.In a patient, a patient is a compound of formula (I). ) or aphannacsuiica31y acceptable salt. Preferably, the immune response is mediated by MHC class ules molecules. The compound of this invention. can be admirdstered prior to, simultaneonsly. or after the therapy. Preferablv, therapy iovolves treatment with a biologic. Preferably, the therapy involves treatment of small molecules.

[0014] Preferably, the biologic is a protein, preferably an antibody, more preferably a monoclonal antibody. More preferrably, the biologic is Remicade®, Refacto®, Referon-A®, Factor VHI, Factor VH, Betaseron®, Epogen®, Enbrel®, īnterferon beta, Βοΐοχ®,Preferably, the biologic is a protein, more an antibody, more preferably a monoclonal antibody. More preferrably, the biologic is Remicade®, Refacto®, Referon-A®, Factor VHI, Factor VH, Betaseron®, Epogen®, Enbrel®, interferon beta, Βοΐοχ®,

Fabrazyme®, Elspai®, Cerezyme®, Myobioc®, Aldurazyme®, Verluma®, īnterferon alpha, Humira®, Aranesp®, Zevalin® or OKT3.Fabrazyme®, Elspai®, Cerezyme®, Myobioc®, Aldurazyme®, Verluma®, interferon alpha, Humira®, Aranesp®, Zevalin® or OKT3.

[0015] Preferably, the treatment involves use of heparin, low molecular weight heparin, procainamide or hydralazine.Preferably, low molecular weight heparin, procainamide or hydralazine.

[0016] In a sixth aspect, this invention is directed to a'method of treating immune response in an animal that is caused by adminislration of a biologic to the animal which method comprises administering to the animal in need of such treatment a therapeutically efiective amount of a compound of Fonnula (1} or a pharmaceutically acceptable salt thereof. 5 5 LV 13669 [0017] In a seventh aspect, this invention is directed to a method of conducting a clinical trial for a biologic comprising administering to an individual participating in the clinical trial a compound of Formula (Γ) or a pharmaceutically acceptable salt thereof with the biologic.A sixth aspect of the treatment of the immune response to the animal, which is a method of treatment of the animal. of a compound of the Fonnula 5 5 EN 13669 In a seventh aspect, a method of conducting a clinical trial for a biologic is administered. Clinical trial of a compound of Formula (Γ) or a.

[0018] In an eigth aspect, this invention is directed to a method of prophylactieally treating a patient undergoing treatment with abiologic with a compound of Formula (1) or a phaxmacentically acceptable salt thereof to treat the immune response caused ’oy the biologic in the patient.In a eigth aspect, a method of treating a patient undergoing treatment with a biochemistry with a compound of Formula (1) patient.

In a ninth aspect, this invention is directed to a method of detenning the loss in the efncacy of a biologic in an animal due to the irumune response caused by the biologic comprising administering the biologic to the animal in the presence and absence of a compound of Formula (I) or apharmaceutically acceptable salt thereof.In a ninth aspect of a biology in a ninth aspect of a biology, a biology of a biology in the body Formula (I) or apharm a acceptable salt.

[0020] In a tenth aspect, this invention is directed to a method of improving ef5cacy of a biologic in an animal comprising administering the biologic to the animal v/itb a compound of Formula (I) or a ph2iniaceutically acceptable salt thereof.[0020] In a tenth aspect, a method of improving the biological activity of an animal is a compound of formula (I) or a ph2iniaceutically acceptable salt.

[0021] In an eleventh aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. Prefsrabiy, the medicament is for use in the treatment of a disease mediated by Cathepsin S.[0021] In an eleventh aspect, the present invention is directed to the use of a medicament. Prefsrabiy, the medicament is for use in the treatment of a disease mediated by Cathepsin S.

[0022] 3n a twelfih aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for ihs manufacture of a medicament for combination therapy wita a biologic, wherein the compound of this invention treats the iromune response caused by the biologic. Preferably, the compound(s) of the invention is administered prior to the administration of the biologīcal aģent Preferably, the compound(s) of the invention is administered concomitantly with the biologīcal aģent. Preferably, the compound(s) of the invention is administered after the administration of the biologīcal aģent.3: a twelfih aspect of the invention of the compound of the invention. iromune response caused by the biologic. Preferably, the compound of the invention is administered concomitantly with the biologic agent. Preferably, the compound of the invention is administered after the administration of the biologic agent.

Detailed Pescription of the Invention D.efLnitions: [0023] Unless otherwise stated, the following teims used in the specification aud claims are defined for the purposes of this Application and have the following meanings. 6 [0024] &quot;AJicyclic&quot; means a moiety characterized by anrang ement of the carbon atoms in closed non-aromatic ring structures e.g., cycloaliyl and heterocycloalkyl rings as defined herein.Detailed Description of the Invention D.efLnitions: [0023] Unless otherwise stated, the following claims are made. 6 &quot; AJicyclic &quot; cycloalyl and heterocycloalkyl rings as defined herein.

[0025] &quot;A!kyl&quot; represented by itself meaas a siiaigbt or branched, saturated aliphatic radical containiag ons to eigbt carbon atoms, nnless otherwise indicated e.g., atkyl metodes methyl, ethyl, propyl, isopropy3, butyl, sec-butvl, isobutyi, teriAmtjl, and the like.&Quot; A! Kyl &quot; Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, teriAmtjl, and the like.

[0925] &quot;AIkylene’', unless indicated oiherwise, means a straight or branched, saturated aliphatic, divalent radical having the number of one to six carbon atoms, e.g., meihylene (-CH2O1 ethylene (-CH2CH2-), trimethylene (-CH2CH2C%-), tetramethylene (-CH2CH2CH2CH2-) 2-methyltetramethylene (-CH2CH(CH3)CH2CH2-), pentamethylene (-CH2CH2CH2CE7CH,-), and the like.[0925] &quot; AIkylene ', unless indicated by an aliphatic, divalent radical having the number one to six carbon atoms, eg, meihylene (-CH2O1 ethylene (-CH2CH2-), trimethylene (- CH2CH2C% -), tetramethylene (-CH2CH2CH2CH2-) 2-methyltetramethylene (-CH2CH (CH3) CH2CH2-), pentamethylene (-CH2CH2CH2CE7CH, -), and the like.

[0027] &quot;Alkylsiiifonyl&quot; means -S02Rradical where R is alkyl as defined herein e.g., methylsulfonyl, eihylsulfonyl, and the like.&Quot; Alkylcarbonyl &quot; means -SO 2 Rradical where R is alkyl as defined herein, methylsulfonyl, nemhylsulfonyl, and the like.

[0028] &quot;AIkylsulfonylsminon means -NHS02Rradical rvhere R is alkyl as defined herein e.g., methylsulfonylamino, ethylsuīfonylamino, and the like.&Quot; Alkylsulfonylminone means -NHSO2Rradical Rf is as defined herein, for example, methylsulfonylamino, ethylsuylphenylamino, and the like.

[0029] &quot;Aficoxy&quot; refers to a-OR radical \vhere R is an alkyl group as defined above e.g., methoxy, ethoxy, and the like.&Quot; Aficoxy &quot; refers to a-OR radical v. R is an alkyl group as defined above, methoxy, ethoxy, and the like.

[0030] &quot;Alkoxyalkyl&quot; means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substitoted vrith at least one alkoxy group, preferably one or iwa alkoxy groups, as defined above, e.g., 2-methoxy-ethyI, l-,2-, or 3-metboxypropyl, 2-ethoxyethyl, and the like.&Quot; Alkoxyalkyl &quot; 1, 2-methoxy-ethyI, as defined above, eg, 2-methoxy-ethyI, means a linear monovalent hydrocarbon radical of one to six carbon atoms. l-, 2-, or 3-methboxypropyl, 2-ethoxyethyl, and the like.

[0031] &quot;-Alkoxycarbonyl&quot; refers to a-C(0)ORradical where R is an alkyl group as defined above e.g., methoxycarbonyl, ethoxycarbonyl, and the like.&Quot; -Alkoxycarbonyl &quot; refer to a-C (O) ORradical where R is an alkyl group as defined above, methoxycarbonyl, ethoxycarbonyl, and the like.

[0032] ”Aminoallcyr' means a linear monovalent hydrocaxbon radical of one to six carbon atoms or a branched monovalent hydrocarbcn radical of three to six carbons substituted vrith at least one, preferably one or two, -NRR’ where R is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxya]kyl, aryl, aralkyl, heteroaryl, heteioaralkyl or heterocycloalkylalkyl andR is hydiogen, alkyl, hydroxyalkyl, alkoxya!kyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, or aminosulfonyl as LV 13669 defined herein e.g., aminomethyl, methylaininoeĪhyl, dimethvlaminoethyl, 1,3-diaminopropyl, acetylamiaopropyl, and the liks."Aminoallcyr" means a linear monovalent hydrocarbons radical of one to six carbon atoms or a branched monovalent hydrocarbons radical of three to six carbons substituted by at least one, preferably one or two, -NRR 'where R is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxy] yl, aryl, aralkyl, heteroaryl; defined herein, aminomethyl, methylaininoethyl, dimethvlaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the residue.

[0033] &quot;Acyri refers to a -COR radical where R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, axalkyl3 heteroaiyl, heĪeroaralkyl, or heierocycloalkyl as defined herein, e.g., fonnyl, acetyl, trifluoroacetyl, benzoyl, piperazin-l-ylcarbonyl, and the like. Wben R is alkyl it is refened to in this application as alkylcarbonyl.&Quot; Acrylic to a -COR radical where R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, axalkyl3 heteroaryl, heroeraralkyl, or heterocycloalkyl as defined herein, e.g., phonnyl, acetyl, trifluoroacetyl, benzoyl, piperazine-l- ylcarbonyl, and the like. Wben R is alkyl it is refined to this application as alkylcarbonyl.

[0034] &quot;Acyialkyl&quot; means a linsar monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocaibon radical of ihree to six carbons substituted witb at least one, preferably one or two, acyl group(s) as defined berein e.g., metbylcarbonylmetbyl, benzoylethyi, piperidin-l-ylcarbonylniethyl or eihyl, and the like.&Quot; Acyialkyl &quot; means a lignar monovalent hydrocarbon radical of one carbon atoms or a branched monovalent hydrocarbons radical of six carbons substituted by at least one, one or two, acyl group (s) as defined berein, metbylcarbonylmethyl, benzoyl, piperidine l-ylcarbonylniethyl or eihyl, and the like.

[0035] &quot;AminocarbonylM means -CONRR’radical where R and R! are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cr hsterocycloalkyiaIlcyl or R and R’ togeiher with the nitrogen atom to vrfiich they are attached fonu heierocycIoamino as defined herein.&Quot; AminocarbonylM means -CONRR'radical where R and R! are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cr hsterocycloalkylaIlcyl or R and R 'togeiher with the nitrogen atom to vrfiich they are attached to the background.

[0036] &quot;Andnosulfonvl&quot; means -SO2NRR’ radical tvhere R and R’ are independently selected from hydrogen, atkyl, aryl, aralkvļ, beteroaryl, heteroarahcvl, or heterocycloaIkylalkyl or R and R’ togeiher rviih the nitrogen atom to which they are attached form heterocycloamino as defined herein.&Quot; Andnosulfonvl &quot; means -SO2NRR 'radical tvhere R and R' are independently selected from hydrogen, aryl, aryl, aralkyl, beteroaryl, heteroarahcvl, or heterocycloalkylalkyl or R and R 'to form a nitrogen atom to which they are attached form heterocycloamino as defined herein.

[0037] &quot;Animal&quot; inclndes humāns, non-huraanmannnals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).&Quot; Animal &quot; inclndes humane, non-huraanmannnals (eg, dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (eg, birds, and the like).

[0038] &quot;Aromatic&quot; refers to a moiety vvherein the constituent atoms make up an unsaturated ring system, ali atoms in ihe ring system are sf hybiidized and the rotai number of pi electrons is equal to 4n+2.&Quot; Aromatic &quot; ibid., i.e., i.e., i.e., i.e., i.e., i.e., i.e., i. e.

[0039] &quot;Aiyl&quot; refers to a monocyclic or iused bicyclic ring assembly containing 6 to 10 ring carbon atoms wherein each ring is aromatic e.g., phenyl or naphthyl.&Quot; Aiyl &quot; containing a monocyclic or iused bicyclic ring assembly containing 6 to 10 ring carbon atoms, each ring being aromatic, e.g., phenyl or naphthyl.

[0040] &quot;Aryloxy&quot; refers to a -O-R radical where R is aiyl as defined above e.g., phenoxy, napthyloxy, and the like.&Quot; Aryloxy &quot; refer to a -O-R radical where R is as defined above, phenoxy, napthyloxy, and the like.

[0041] &quot;AryloxycarbonyT refers to a -C(0)OR radical where R is aryl as defined above e.g., phenyloxycarbonyl, naphthyloxycarbonyl, and the like. 8 [0042] &quot;Axalkyl&quot; reiers ίο a -(alkylens)-R radical vhere R is aiyl as defined above e.g., benzyl, phenethyl, and the like.&Quot; AryloxycarbonyT refers to a -C (O) OR radical where R is aryl as defined above, phenyloxycarbonyl, naphthyloxycarbonyl, and the like. 8 &quot; Axalkyl &quot; reiers ίο a - (alkylene) -R radical v is as defined above, benzyl, phenethyl, and the like.

[0043] MAraIky]oxy&quot; refers to a -O-R radical where R is aralkyl as defined above e.g., benzyloxy, phenethyloxy, and the like.MAraIky] oxy &quot; refer to a -O-R radical where R is aralkyl as defined above, benzyloxy, phenethyloxy, and the like.

[0044] ,'Axalkyloxycarbonyl&quot; refers to a -C(0)OR radical where R is axalkyl as defined above e.g., benzyloxycafbon.yl, pheneihyloxycafbonyl, and the like., Axalkyloxycarbonyl &quot; refer to a -C (O) OR radical where R is axalkyl as defined above, benzyloxycafbon.yl, pheneihyloxycafbonyl, and the like.

[0045] ' “Biologic” means a therapeuiic aģent originally deiived from living organisms for the treatment or management of a disease, Bxamples include, but are not limited to, proteīns (recombinani and plasma derived), monoclonal or polyclonal, hmnanized or murine antibodies, toxins, honnones, and the like, Biologīcs are ciirrently available for the treatment of a vaxiety of diseases such as cancer. rheumatoid anhritis, and hemophilia.Bxamples include, but are not limited to, protein, recombinant and murine antibodies. , toxins, honnones, and the like, Biologicals are ciirrently available for the treatment of diseases such as cancer. rheumatoid anhritis, and hemophilia.

[0046] &quot;Carboxy&quot; refers to -C(0)OH radical.&Quot; Carboxy &quot; refers to -C (0) OH radical.

[0047] &quot;CycIoaIkyr' refers to a mono valenr satorated monocyclic ring containing fbree to eight ring carbon atoms e.g., cyclopropyl, cydobuiyl, oyclopentyi, cyclohexyi, and the like.&Quot; CycloaIkyr &quot; refers to a mono valentine monocyclic ring containing fbree to eight ring carbon atoms, e.g., cyclopropyl, cydobuiyl, oyclopentyi, cyclohexyi, and the like.

[0048] &quot;CycIoaBcylalkyr refers to a -(aikylene)-S. radical v/here R is cycloalkyl as denned above e.g., cyclopropylmeihyl, cyclobutyiethyl, cycIobuiytnetbyl, and the like.&Quot; CycIoaBcylalkyr refers to a - (alkylene) -S. radical v / here R is cycloalkyl as denned above, cyclopropylmeihyl, cyclobutyiethyl, cycIobuiytnetbyl, and the like.

[0049] ''CycloaIkyIoxycarbGīiyr' refers to a -C(0)OR radical vriiere R is cyccloa!kyl as defined above e.g,, cyc!opropyloxycarbonyl, cyclopentyIoxycaibonyl. and the like."CycloalkyloxycarbGiyr" refers to a -C (O) OR radical sulfurylcycloalkylcycloalkylcycloalkyl, cyclopentyIoxycaibonyl. and the like.

[0050] &quot;Cycloalkylene&quot; refers to a divalent satorated monocyclic ring containing three to eight ring carbon atoms. For example, the instance v/herein &quot;R3 and R4 together with the carbon atom to which both R and R* are attached foim cycloaIky!ene&quot; includes, but is not limited to, the follovring: Δ.&Quot; Cycloalkylene &quot; refers to a divalent satorated monocyclic ring containing three to eight ring carbon atoms. For example, the instance v / i &quot; R3 & R4 together with the R & R * are attached to the main cycloaIky! Ene &quot; includes, but is not limited to, the follovring: Δ.

and the like.and the like.

[0051] &quot;Disease&quot; specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the &quot;side effects&quot; of such therapy. 9 9 LV 13669 [0052] “Derived” means a similar aģent can be traced to.&Quot; Disease &quot; special includes any unhealthy condition or anthropogenic condition, of such therapy. 9 9 EN 13669 “Derived” means a similar agent can be traced to.

[0053] “Deleterious immune response” means an iīnmune response that pievents effective treatment of a patient or causes disease in a patieni. As an example, dosing apatient vvith a murine antibody either as a therapy or a diagnostic aģent causes the production ofhuman antimouse antibodies that prevent cr interferev/ith subsequent treatments. The incidence of antibody formation versus pure murine monoclonals can exceed 70%. (see Khazaeli, Μ. B. et al. J. īmmunother. 1994,15, pp 42-52; DillmanR. O. et al. Cancer Biother. 1994, 9, pp 17-28; and Reinsberg, J. Hybrido?na. 1995,14, pp 205-208). Additional examples of known aģents that suffer from deleterious immune responses are blood-clotting factors such as factor V3H, When administered to hemophilia A patients, factor VHI resiores the ability of the blood to clot. Although factor VHI is a human protem, it stili elicits an immune response in hemophiliacs as endogenous factor VHĪ is not preseni in theii blood and tīrus it appears as a foreign antigen to the immune system. Approxiiaately 29-33% of new patients will producē antibodies that bind and neutraJize the therapeutically administered factor Vm (see Lusher J. M. Semin Thromb Hemost. 2002,28(3), pp 273-276). Thess neutralizing antibodies reguire the adramistration of larger amounts of factor ΥΪΠ in order to maintain nonnal blood clotting parameters; an espensive regimen of treatment in order to inducē immune tolerance (see Briet E et ai. Adv. Exp. Med. Bio. 2001,489, pp 89-S7). Anoiher immunogenic exampie is adenoviral vectors. Retrovirsl therapy remains expeximental and i-s of limited uti3ity. One reason is that the applicaiion of a therapeutic rirus generates an inunune response capable of blocking any subsequent administration of the same or similar viras (see Yiping Yang et al. J. ofVirology. 1995, 69, pp 2004-2015). This ensures that retroviral therapies must be based on the transient expression of a protein or the dimot incorporation of -virai sequence into the bosi genome. Diiected research has identified multiple virai neutralizing epitopes recognized by host antibodies (see Hanne, Gahery-Segard et al. J. of Virology 1998. 72, pp 2388-2397) suggesting that virai modifications will not be sufBcient to overcome this obstacle. This invention will enable a process whereby an adenoviral therapy will havs utility for repeated application. Another example of an immunogenic aģent that elicits neutralizing antibodies is the well-known cosmetic aģent Botox. Botulin toxin protein, is purified from the fennentation of Clostridium botulinum. As a therapeutic aģent, it is used for muscle disorders such as cervical dystonia in addition to cosmetic application. After repeated exposuxe patients generate neutralizing antibodies to the toxin that results inreduced efticacy (see Birldein F. et al. Ann Neurol. 2002,52, pp 68-73 and Rollnik, J. D. et al. Nevrol. Clin. 10[0053] "Deleterious immune response" means a response to a patient or cause disease in a patient. As an example, dosing apathetic vvith a murine antibody or a diagnostic agent that prevent cr interferev / ith ongoing treatments. The incidence of antibody formation versus pure murine monoclonals can exceed 70%. (see Khazaeli, B.B. et al., J.Mymmunother. 1994, 15, pp. 42-52; Dillman R. O. et al. Cancer Biother. 1994, 9, pp. 17-28; and Reinsberg, J. Hybrido? na. 1995,14, pp. 205-208). Additionally, there is a factor in the development of blood-clotting factors such as factor V3H. Though factor VHI is also a human protemic strain, as well as an endogenous factor in the endocrine system. Approxiiaately 29-33% of new patients will be producing antibodies and binders (see Lusher J.M. Semin Thromb Hemost. 2002.28 (3), pp. 273-276). Thess neutralizing antioxidants; (see Briet E et al. Adv. Exp. Med. Bio. 2001,489, pp. 89-S7). Anoleher immunogenic exampie is adenoviral vectors. Retroviral therapy remains expexitional and i-s of limited uti3ity. One reason is that a response to the same or similar viruses (see Yiping Yang et al. J.Virology. 1995, 69, pp. 2004-2015). This is a botanical genome. (See Hanne, Gahery-Segard, et al., J. of Virology, 1998, 72, pp. 2388-2397) suggesting that virai modifications will not be sufBcient to overcome this obstacle. This invention will provide a process for the treatment of adenoviral therapy. Another example of an immunogenic agent is botoxic agent Botox. Botulin toxin protein, is a source of Clostridium botulinum. As a therapeutic agent, it is used for the treatment of cystic dystonia in addition to cosmetic application. (See Birldein F. et al., Ann Neurol. 2002, 52, pp. 68-73 and Rollnik, J.D. et al., Nevrol Clin.

NaurophysioI. 2001,2001(3), pp 2-4). A “deleterious immune response” also encompasses diseases caused by therapeutic aģents. A specific example of this is the 11101111116 response to therapy with recombinant human eiytliropoietin (EPO). Erythropoietin is nsed to stimulate the growth or of red celis, and restore red blood celi counts in patients who have undergone chemotherapy or dialysis. A small percentage of patients develop antibodies to EPO and subsequently are umesponsive to both therapeutically administered EPO and their own endogenous EPO ('ses CasadevaU, N. ei al, NEJM. 2002,346, pp 469-475). They contract a disorder, pure red celi aplasia, in which red blood celi production is severely dimirdshed {ses Gershon S. K. ei, al. NEJM, 2002,346, pp 1584-1586). This complication ofEPO therapyis lethal if nntreated. Another specific example is the marinē antibody, OKT3 (a.k.a., Orthoclone) a monoclonal antibody directed towards CD-3 domam of activated T-cells. In clinical trials 20-40% of patients administered OKT3 producē antibodies versus the therapv. These antibodies, besides neutralizing the therapy, also stimulate a stronghost immune reaction. The immune reaction is severe enough that patients vrith high titers of human anti-mouse antibodies are specifically restricted fiom taking the drug {see Orthoclone ņackags lahel). A final example is ahuman antibody therapeuric. Humira® is amonoclonal antibody directed against TNF and is used to treat rheumatoid arthiitis patients. Wh.en. taken alone . ~12% of patients develop neutralizing antibodies. In additior, a small percentage of patients . given the drug also contract a systemic lupus erthematosus-like condition that is an īgG-mediated komune response induced by the therapeutic aģent {ses Humira packaģe lahel).NaurophysioI. 2001,2001 (3), pp. 2-4). The "deleterious immune response" also encompasses diseases caused by a therapeutic agent. Response to therapy with recombinant human nonytliropoietin (EPO). Erythropoietin is nsed to stimulate the growth or red cell counts in patients who have undergone chemotherapy or dialysis. EPO and their own endogenous EPO ('ses CasadevaU, N. N. al., NEJM. 2002,346, pp. 469-475). They contract a disorder, pure red cell aplasia, in Gershon S. K., al., Al. NEJM, 2002,346, pp. 1584-1586). This complication ofEPO therapyis lethal if nntreated. Another specific example is the marinating antibody, OKT3 (a.k.a., Orthoclone), a monoclonal antibody directed towards CD-3. In clinical trials 20-40% of patients administered OKT3 produces antibodies versus the therapv. These antibodies, besides neutralizing the therapy, also stimulate a stronghost immune reaction. This is the Orthoclone ackags bay. Final example is ahuman antibody therapeuric. Humira® is an amonoclonal antibody directed against TNF and is used to treat rheumatoid arthritis patients. Wh.en. taken alone. ~ 12% of patients develop neutralizing antibodies. In additior, a small percentage of patients. The drug is also known as the 'Humira packaģe'.

[0054] Another example of “deleterious iimnune response” is a host reaction to small molecule dmgs. It is knov/n to those skūled. in the art that certain Chemical structures will conjugate with host proteīns to stimulate immune recognition (see Ju. C. ei al. 2002. Currer.t Drug Metabolism 5, pp 367-377 and Kimber I et al. 2002, Toxicologic Pathology 30, pp 54-58.) A suhstantial portion of these host reactions are IgG mediated. Specific “deleterious immune responses” that are IgG mediated include: hemolytic anemia, Steven-Johnson syndrome and drug induced Lupus.Another example of a "deleterious iimnune response" is a host reaction to small molecule dmgs. It is knov / n to those shaves. Chemical structures will conjugate with host protein to stimulate immune recognition (cf. Ju. C. no. 2002. Currer.t Drug Metabolism 5, pp. 367-377 and Kimber I et al., 2002, Toxicologic Pathology 30, pp 54-58.) A proportion of these host reactions are IgG mediated. Specific "deleterious immune responses" that are IgG mediated include: hemolytic anemia, Steven-Johnson syndrome and drug induced Lupus.

[0055] &quot;Halo&quot; refers to fluoro, chloro, bromo or iodo.&Quot; Halo &quot; refers to fluorine, chlorine, bromine or iodine.

[0056] &quot;Haloalkyl&quot; refers to alkyl as defined above substituted by one or more, for example from one to thirteen, preferably fiom one to seven, &quot;halo&quot; atoms, as such terms are defined in this Application. Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl . 11 11 LV 13669 and the liks e.g. cMoromethyl, dicMoromethyl, difluoroinethyl, trifluoromethyl, 2,2,2-trifluoroefhyl, perfluoroe!hyl, 2,2,2-irifiuoro-l,l-dicMoroethyl, and the like.&Quot; Haloalkyl &quot; for one to seven, &quot; halo &quot; atoms, as such. Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl. 11 11 EN 13669 and the liks e.g. cMoromethyl, dicMoromethyl, difluoroethyl, trifluoromethyl, 2,2,2-trifluoro-phenyl, perfluoroacetyl, 2,2,2-irifluoro-l, l-dicororoethyl, and the like.

[0057] &quot;Haloalkylene&quot; means alkylene radical as defined above wherein one to four, preferably one or two hydrogen atoms in the alkylene chain has(have) been replaced by fluorine atom(s).&Quot; Haloalkylene &quot; One of four hydrogen atoms in the alkylene chain is a fluorine atom (s).

[O05S] &quot;Ha3oalkoxy&quot; refers to ,a -OR radical where R is haloalkyl group as defined above e.g., trifluoromeihoxy, 2,2,2-trifluoroethoxy, difluorome1hoxy, and the liks.[O05S] &quot; Ha3oalkoxy &quot; refers to, -OR radical where R is haloalkyl as defined above, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the liks.

[0059] &quot;Heteroaiyl&quot; as a group or part of a gronp denotes an aromatic monocyclic or bicycbc moiety of 5 to 10 ring atoms in wMch one or raore, preferably one, two, or three, of the ring atom(s) is(are) selected from nitrogen, oxygen or sulfirr, the remaining ring atoms being carbon. Representative heteroaryl rings include, but are not liraited to, pyirolyl, ihranyl, thienyl, oxazolyl. isoxazolyI, thiazolyl, imidazolyl, triazoIyI, tetrazolyl, pyridinyl, pyriraidinyl, pyrazinyl, pyrfdazinyl, indolyl, benzofuranyl, benzothioplienyl, benziroidazolyl, quinolinyl, isoquinoIinyl, quinazolinyl, qninoxalinyl, pyrazolyl, and the like.&Quot; Heteroyl &quot; as a group of atoms, in one or two of the ring atom (s) is selected from nitrogen, oxygen or sulfirr, the remaining ring atoms being carbon. Representative heteroaryl rings include, but are not liraited to, pyirolyl, ihranyl, thienyl, oxazolyl. isoxazol, thiazolyl, imidazolyl, triazoyl, tetrazolyl, pyridinyl, pyrrolidinyl, pyrazinyl, pyrfdazinyl, indolyl, benzofuranyl, benzothiophenyl, benziroidazolyl, quinolinyl, isoquinoinyl, quinazolinyl, qninoxalinyl, pyrazolyl, and the like.

[0060] &quot;ΗεΐεΓΟβχγΙοχ'/’ refers to a -O-R radical vhere R is heteroaxyl as defined above e.g., fūianyīoxy, pyridinvloxy, indolyloxy. and tbe like.&Quot; ΗεΐεΓΟβχγΙοχ '/' refer to a -O-R radical v is heteroaxyl as defined above, fyria, pyridinvloxy, indolyloxy. and tbe like.

[0061] &quot;Heteroaiyloxycarbony]” refers to a -C(0)0-R radical where R is heteroaxy! as defined above e.g., pyri&lt;3iny!oxycarbonyI, pyriinidinyloxycarbonyl, and the like.&Quot; Heteroaiyloxycarbony] ”refers to a -C (0) 0-R radical where R is heteroaxy! as defined above., &lt; 3iny! oxycarbony, pyriinidinyloxycarbonyl, and the like.

[0062] &quot;Heteroaralkyl&quot; refers to a -(aīkylene)-R radical where R is heteroaxyl as defined above e.g., pyridinylmeihy3,1- or 2-furanylethyl, inridazolylmethy3, and the like.&Quot; Heteroaralkyl &quot; refers to a - (aylene) -R radical where R is heteroxyl as defined above, pyridinylmihy3,1- or 2-furanyl, inridazolylmethy3, and the like.

[0063] &quot;Esieroaxalkyloxy&quot; refers to a -O-R radical vrhere R is heieroaralkyl as defined above e.g., pyridinyhneihyioxy, furanyīethyIoxy. and the like.&Quot; Esieroaxalkyloxy &quot; refer to a -O-R radical v is H eeroaralkyl as defined above, pyridinyhneihyioxy, furanyethyoxy. and the like.

[0064] &quot;Heteroaralkyloxycarbonyl&quot; refers to a -C(0)0-R radical where R is heteroaralkyl as defined above e.g., pyridinyhnefhyloxycarbonyl, pyrirrūdinyhnetliyloxycarbony3, and the like.&Quot; Heteroaralkyloxycarbonyl &quot; refers to a -C (O) 0-R radical where R is heteroaralkyl as defined above, pyridinyhnefhyloxycarbonyl, pyrirrubinhnetliyloxycarbony3, and the like.

[0065] &quot;Heterocycloalkyr refers to a saturated or paitiaHy unsaturated, mono or bīcyclic radical of 4, 5 or 6 carbon ring atoms wherein one or more, preferably one, two, or three of the ring carbon atoms are replaced by a heteroatom selected from -N=, -N-, -O-, -S-, -SO-, or -S(0)z- and furiher vvherein one or two ring carbon atoms are optionally replaced by a keto (-CO-) group. The heterocycloalky] ring is optionally fiised to cycloalkyl, aryl or fieteroaiyl 12 ring as defined bereim Representative examples include, but axe not limited to, iimdazo]idiiiyl, moxp3iolinyl, thiomorplioliiiyl, thiomorpholino-l-oxide, thiomoipholino-1,1-dioxide, tetrahydrofcranyl, tetrahydropyranyl, tetrahydrofhiopyraayl, l-oxo-tetrahydrothiopyranyl, l,l-dioxotetratliio-pyranyl, indolinyl, piperazinyi, piperidyl, pyrrohdinyl, pyirolinyl, qumuclidmyl,3I4-dxhydroisoquinoliriyl: dihydroindolyl, and the liks.&Quot; Heterocycloalkyr to a saturated or paitHy unsaturated, mono or bicyclic radical of 4, 5 or 6 carbon ring atoms, or one, two, or three of the ring carbon atoms are replaced by a heteroatom selected from -N =, -N-, -O-, -S-, -SO-, or -S (0) z- and furiher vvherein one or two ring atoms are optional replaced by a keto (-CO-) group . The heterocycloalky] ring is optional for cycloalkyl, aryl or diethyl aryl 12 ring defined for example, but not limited to, iimdazo] idyl, moxypolyolinyl, thiomorpholyl, thiomorpholino-1-oxide, thiomipholino-1,1-dioxide, tetrahydrofranyl, tetrahydropyranyl, tetrahydrofiopyran, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetratylpyranyl, indolinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolidinyl, qumuclidyl, 3I-dxhydroisoquinoliryl: dihydroindolyl, and the liks.

[0066] When the heterocycloalkyl group contains at least one nitrogen ring atom it is refened to hereia as “heierocycloaniino” and is a subset of the heterocycloalkyl group as defined above.When the heterocycloalkyl group is at least one nitrogen ring it is refined to hereia, as well as a heterocycloalkyl group as defined above.

[0067] &quot;Heterocyclylalkylene&quot; refers to a divalent heterocyclyl group, as defined in this ' Application, e.g., the instance Tvhsrein R3 and R4 together with the cafbon atom to rvhicb both R' and R4 are attached foim heterocyclylalkyiene:: includes, but is not limited to, the following:&Quot; Heterocyclylalkylene &quot; refers to a divalent heterocyclyl group, as defined in this application, eg, the instance of Tvhsrein R3 and R4 together with the cafe atom Rv and R4 are attached to the main heterocyclylalky :: includes, but is not limited to, the following :

in vvhich R is a substituent defined in the Summary of the īnventicn [0068] &quot;HeterocycloaIkylaIkyΓ, refers to a -(alkylene)-R radical v/here R is heterocycloalkyl as defined above e.g., pyxrolidinylmetiiyl, tetrahydioiuranylethy3, pyridinylmethylpiperidinylmethyl, and the like.in vvhich R is a substituent as defined in the Summary of the Invention, refers to a - (alkylene) -R radical or heterocycloalkyl as defined above, pyxrolidinylmethyl, tetrahydrouryllethyl, pyridinylmethylpiperidinylmethyl, and the like .

[0069] ,!Heterocycloalkyloxycarbonyl&quot; refers to a -C(0)OR radical where R is heterocycloalkyl as defined above e.g., pyridinyloxycaibonyl, pyrimidinyloxycaxbonyl, and the like.Heterocycloalkyloxycarbonyl &quot; refer to a -C (O) OR radical where R is heterocycloalkyl as defined above, pyridinyloxycaibonyl, pyrimidinylxycaxbonyl, and the like.

[0070] &quot;Hydroxy&quot; meaos -OH radical. Unless indicated othenvise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.&Quot; Hydroxy &quot; meaos -OH radical. Unless indicated othenvise include protected derivatives; Benzyl and the like.

[0071] &quot;Hydroxya]kyl&quot; means a linearmonovalenthydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydxoxy groups, provided that if two hydroxy groups are present they are not both 13 13LV 13669 on the sarne carbon atom. Representative examples include, but aie not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl) l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 44iydroxybutyl, 2J3-dibydroxypropyl, 1-(hydroxymethyl)42drydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)43-hydroxypropyl, preferably 2-hydroxyetbyl, 2,3-dihydroxypropyl, and 1-(hydroxymetbyl)-2-bydroxyetbyl.&Quot; Hydroxya] Kyl &quot; one of two carbon atoms or a branch of a carbon monoxide atomic nucleus. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl) -1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 44-hydroxybutyl, 2J3-dibydroxypropyl, 1- (hydroxymethyl) 42drydroxyethyl, 2,3-dihydroxy-butyl, 3,4-dihydroxy-butyl and 2 - (hydroxymethyl) 43-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymetbyl) -2-bydroxyetbyl.

[0072] &quot;Isomers&quot; mean compounds of Formula (ļ) having identical molecular fonnulae but differ in the nature or sequence of bonding of their atoms or in the arrangemeni of their atoms in space. Isomers that differ in the arrangemeni of their atoms in space are teimed &quot;stereoisomers&quot;. Stereoisomers that are not nairror images of one another are teimed &quot;diastereomers&quot; and stereoisomers that are nonsuperimposable mirror images are teimed &quot;enantiomers&quot; or sometimes &quot;optical isomers&quot;. A carbon atom bonded to four nonidentical substituents is teimed a &quot;chiral oenter”. A compound with one chiral center that has two enanfiomeric fonus of opposite chirality is teimed a &quot;racemic mixture&quot;. A compound that has more than one chiral center has 2n'] enantiomeric pairs, where n is the number of chiral centers. Compounds vriih more than one ciiral center may exist as either an individual diastereomer or as a mixture of diastereomers, teimed a &quot;diastereomeric mixture”. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangemeni in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and jī-seguencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the detennination of stereochemistry and the separation of stereoisomers are well knovm in the art (e.g., see &quot;Advanced Organic Chemistiy&quot;, 4th ediiion, March, Jeny, John Wiley &amp; Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula (I) are meant to be encompassed ali possible stereoisomers.&Quot; Isomers &quot; mean compounds of Formula (s) having the same molecular fonnulae but different in nature or in the sequence of their atoms in space. Isomers that differ in the order of their atoms in space are teims &quot; stereoisomers &quot;. Stereoisomers that are not nairror images of one another are teimed &quot; diastereomers &quot; and stereoisomers that are nonsuperimposable mirror images are teimed &quot; enantiomers &quot; or sometimes &quot; optical isomers &quot;. The carbon atom bonded to four nonidentical substitutes is a "chiral oenter". The compound with one chiral center is the "racemic mixture". The compound that has more than one chiral center has 2n '] enantiomeric pairs, where is the number of chiral centers. Compounds vriih more than one center of the diastereomers, and a "diastereomeric mixture". When one chiral center is present a stereoisomer may be a chiral center. Attached to the chiral center. Enantiomers are defined by their chiral centers and described by Cahn, Ingold and Prelog. Methods for Stereochemical Nomenclature, Methods for Detection of Stereochemistry and Echinaceae (eg, "Advanced Organic Chemistiy", 4th ediiion, March, Jeny, John Wiley & Sons, New York, 1992) ). It is understood that the names are used in the formula (I) are meant to be encompassed by possible stereoisomers.

[0073] &quot;Optional&quot; or &quot;optionally&quot; or “may be” means that the subsequently described event or circmnstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, ihe pbiase &quot;wherein the aromatic ring in Ra is optionally suhstitutea with one or two substituents independently selected from alkyl” means that the aromatic ring may or may not be substituted with alkyl in order to fall wiihin the scope of the invention. 14 [0074] The present inventioa also includes iV-oxide derivatives of a compound of Formula (3). i7-oxide derivative mean a compound of Formula (I) in %hich anitrogen atom is in an oxidized stats (i.e.; N-*0) e.g., pyxidine iV-onds, and which possess the desired phaimacological activity.&Quot; Optional &quot; or &quot; optional &quot; or "may be" means the event or circumstance that may or may not occur; For example, one of the pbiasis is an aromatic ring in the form of a substitute or an alternative to the term. [0074] The present inventor also includes a derivative of a compound of Formula (3). The α-oxide derivative means the compound of Formula (I) in% hich anthrogen atom in an oxidized stats (i.e., N-O), e.g., pyxidine i-onds, and which possess the desired phaimacological activity.

[0075] &quot;Paihology&quot; of a disease means the essential nature, causes and development of fhe disease as well as the stmctural and fonctional changes that result from the disease processes.&Quot; Paihology &quot; of the disease means the most important cause of disease.

[0076] &quot;Phannaceutically acceptable&quot; means that which is nseful in preparing a phaimaceutic2l composiiion that is generally safe, non-toxic and neither bio!ogically nor othenvise undesirable and includes that which is acceptable for veterinār}7 use as well as humanphaimaceutical use.&Quot; Phannu acceptable &quot; that use is a safe and effective way to reduce the risk of harm to the body. 7 use as well as humanphaimaceutical use.

[0077] &quot;?haimaceutical3y acceptable salts&quot; means salts of compounds of Formula (I) which are phaimaceuiically acceptable, as deSned above, and whičh. possess the desired phaimacological activity. Such salts include acid addition salts fonned fviih inorganic acids such as hyorochloric acid, hydroororaic acid, sulSiric acid, nitric acid, phosphoric acid, and the liks; or λνϊΰι organic acids such as acetic acid, propionic acid. hexanoic acid, heptanGic acid, cvclopentanepropionic acid, glycolic acid, pvruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fomaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydtoxybenzoyI)benzoic acid, dimamie acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, l,2-ethanedisulfonic acid, 2-hydroxy-eihanesulfomc acid, benzenesulfonic acid, y?-chlorob enzenesuhonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-meihylbicyclo[2.2.2]oct-2-ene-l-caxboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-eiis-l-carboxylic acid), 3-phenyipropionic acid, trixnethylacetic acid, tertiary butylacetic acid, lauiyl sidiuric acid, gluconic acid, glutaroic acid, hydxoxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.&Quot;? Haimaceutical3y acceptable salts &quot; which are phaimaceuiically acceptable, as deSned above, and whičh. possess the desired phaimacological activity. Such salts include acid addition salts, hydrororic acid, sulic acid, nitric acid, phosphoric acid, and the liks; acetic acid, propionic acid. hexanoic acid, heptanGic acid, cvclopentanepropionic acid, glycolic acid, lactic acid, malic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydtoxybenzoyi) benzoic 2-ethanedisulfonic acid, 2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 2-ethanedisulfonic acid, 2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid , 4-methylbicyclo [2.2.2] oct-2-ene-1-caxboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenyipropionic acid, trixnethylacetic acid, tertiary butylacetic acid, salicylic acid, glutaric acid, muconic acid and the like.

[0078] Pharmacentīcally acceptable salis also include base addition salts which may be foimed when acīdic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodimn carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A-metbylglucamine and the like. 15 15LV 13669 [0079] The present invention also includes prodrugs of a compound of Foramla (I). Prodrug means a compound that is convertible m vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (Γ). For example, an ester of a compound of Formula (Ϊ) containing a hydroxy group may be convertible by hydrclysis in vivo to the parent molecule. Altematively an ester of a compound of Formula (Γ) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxaīates, salicvlates, propionates, succinaies, fumaraies, maleates, meihylene-bis-Pb-hydroxynaphūioaies, gentisates, isethionates, di-p-toluoyltartrates, methylsulphonates, ethanesulpbonates, benzenesulphonates, p-ioluenesulphonates, cyclobexylsulphamates and quinates. Suitable esters of compounds of Formula (I) containing a carboxy group, are for examp3s those described by Lemweber, F J. DrugMeiab. Res1987,18, page 379. An especially useful class of esters of compounds of Formula (Γ) containing a hydroxy group, may be foimed from acid moieties selected from tbose described by Bundgaard et ai, J. Msd. Chsm., 1989, 32, pp 2503-2507, and include substifuted (aminomeihyl)-benzoaieā, for example, dialkylamino-meihyibeszoates in which the two alkyl groups may be joined togetiier and/or interrupted by an oxygen aiom or by an optionally substitated nitrogen atom, e.g. an alkyiated nitrogen atom, more especialīy (moipholino-rnefhyl)beii2oates, e.g. 3- or4-(moipholinomethyl)'benzoates, and .· (4-alkylpiperazin-1 -yl)benzo ātes, e.g. 3- or 4-(4-alkylpiperazm-l-yl)benzoaĪes.[0078] The present invention also relates to pharmacological agents for use in the manufacture of pharmaceutical compositions and pharmaceutical compositions. Acceptable inorganic bases include sodiumhydroxide, sodimn carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A-metbylglucamine and the like. 15 15LV 13669 [0079] The present invention also includes prodrugs of a compound of Foramla (I). Prodrug means a compound that is convertible in vivo by metabolic means (eg by hydrolysis) to a compound of Formula (Γ). For example, an ester of a compound of Formula (Ϊ) containing a hydroxy group may be convertible by hydrclysis in vivo to the parent molecule. Altematively an ester of a compound of formula (Γ) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula (I) containing a group of examples of acetates, citrates, lactates, tartrates, malonates, oxaates, salicvates, propionates, succines, fumarioses, maleates, meihylene-bis-Pb-hydroxynaphyose, gentisates, isethionates , di-p-toluoyltartrates, methylsulphonates, ethanesulpbonates, benzenesulphonates, p-ioluenesulphonates, cyclobexylsulphamates and quinates. Suitable esters of compounds of Formula (I) containing a carboxy group, described by Lemweber, F J. DrugMeiab. Res1987,18, page 379. Containing a group of compounds of the formula (Γ) containing a group of compounds described by Bundgaard et al., J. Msd. Chsm., 1989, 32, pp. 2503-2507, and include substifuted (aminomeihyl) benzoate, for example, dialkylamino-meihyibesoates and / or interrupted by an oxygen substitute nitrogen atom, eg an alkyiated nitrogen atom, more especialīy (moipholino-rnefhyl), e.g. 3- (4-methylpiperazinyl) benzoates, and (4-alkylpiperazin-1-yl) benzoates, e.g. 3- or 4- (4-alkylpiperazm-1-yl) benzoic acid.

[0080] &quot;Protected derivatives&quot; means derivatives of componnds of Formula (Γ) in v/hich a reactive site or sites are blocksd vviih protecting groups. Protected derivatives of compounds of Formula (ļ) are usefiil in the preparation of compounds of Formula (I) or in themselves may be active cathepsin S inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999.&Quot; Protected derivatives &quot; means of componnds of Formula (Γ) in v / hich a reactive site or sites are blocksd vviih protecting groups. Protected derivatives of the Formula (s) are used as an inhibitor of the Formula (I) or in themselves may be active cathepsin S inhibitor. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999

[0081] &quot;Therapeutically effective amount&quot; means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treafment for the disease. 16 16 LV13699 [0082] &quot;Treatment&quot; or &quot;treating&quot; .means any admimstration of a compound of the present invention and includes: (1) preventing the diseass fiom occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or syxnptomatology of the disease, (2) inbibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., airesting forther development of the pathology and/or symptomaiology), or (3) ameliorating the disease in an animal that is expeiiencing or disp!aying the pathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology). &quot;Treatment&quot; or &quot;treating&quot; with respect to combination therapy i.e,, use v/ith a hiologic means any admimstration of a compound of the present invention and includes: (1) preventing the inrmrme response from occurring in an animal which may be predisposed to the immune response but does not yet experience or display the pathology or symptomatology of the iromuiie response, (2) inhibiting the immune response in an animal that is experiencmg cr displaying the paihology or s&gt;mptomaiolcgy of the im-mane response (i.e.. airesting forther development of the pathology and/or symptomatology), or (3) ameliorating the immume response in an animal that is experiencing or aisplaying the pathology or symptomatology of the imnmne response (i.e., reducing in degree or severity, or extent or duration, the overt manifesiations of the immune response or reversing the paihology and/or symptomaiologye.g., reduced binaing and presentation of antigenic peptides by MHC class Π molecules, reduced activation of T-cells and B-cells, reduced humoral and cell-mediated responses and, as appropriate to the pariicular iromune response, reduced inflammation, congestiou, pain, necrosis, reduced loss in the efScacy of a hiologic aģent, and the lilce).&Quot; Therapeutically effective amount &quot; that is the amount of the disease; 16 16 LV13699 &quot; Treatment &quot; or &quot; treating &quot; .means any admimstration of a present invention: (1) inbibiting the disease that is experiencing or displaying the pathology or symptomology of the disease, or (3) ameliorating the disease. the pathology or symptomatology of the diseased (ie, reversing thepathology and / or symptomatology). &quot; Treatment &quot; or &quot; treating &quot; with respect to the use of a substance or a combination of the following: (1) (2) inhibiting the immune response in the animal that is experiencmg. or or symptomatology), or (3) ameliorating the immune response of the immune response (ie, orthodontic manifestations of the immune response). or reversing the paediatrics and / or symptomology of the antigenic peptides by MHC class ules molecules, reduced activation of T-cells and B-cells, and reduced lymphocyte response, and reduced lymphocyte response, and the lilce).

[0083] The expression “wherein the aromatic or ahcyclic ring in R5 is optionaIly substituted with one, two, or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alky], haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from hydroxyaUryl, alkoxyalkyl, aminoa]ky!, aiyl, heteroaiyl, aralkyl, heteroaralķri, cycloalkyl, cycloalkylalkyl,.............” in the defedtion of R5 in the compound of Formula (1) means that ali the aromatic and alicyclic rings within the scope of ' 17 ' 17LV 13669 R5 wbether directly or indirectly attacbed (e.g., R5 is cycloalkylalkyl, -allcylene-X-R9 where X is as defined io the Sunimaiy of the Invention and R9 is ary, aralkyl, etc,..) aie optiona!ly substituted v/ith Ra, or Rb and Rc, or Rc alone.[0083] The expression "aromatic or ahcyclic ring in R5 is optionally substituted with one, two, or three Ra or selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; selected from hydrogen, alky], haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from hydroxyaUryl, alkoxyalkyl, amino] alkyl, alkyl, heteroaryl, aralkyl, heteroaracryl, cycloalkyl, cycloalkylalkyl, ............. "in the deflection of R5 in the compound of Formula (1) means that the aromatic and alicyclic rings within the scope of '17' 17LV R5 wbether directly or indirectly attacbed (eg, R5 is cycloalkylalkyl, -cylene-X-R9 wherein X is as defined in the Invention and R9 is ary, aralkyl, etc.) Ra, or Rb and Rc, or Rc alone.

Preferred Embodiroents [0084] I Cērtam compounds of Formula (I) witbin the broadest scope set fortb in the Summaryof tbe Invention are preferred. Forexample: (A) A preferred group of compounds is that wherein: R1 is hydrogen or methvl, preferably bydrogen;Preferred Embodirents I Certam compounds of Formula (I) witbin the broadest scope set fortb in the summaryof tbe Invention are preferred. Forexample: (A) R 1 is hydrogen or methvl, preferably bydrogen;

R2 is cyciopropyl, l-phenyleihyl [-CH(CsIi5)CH3], or lif-pyrazol-5-yl; prefsrably cyclopropyLR 2 is cyclopropyl, 1-phenyleyl [-CH (C 1-5) CH 3] or orthoprazole-5-yl; prefsrably cyclopropyL

[0085] (1) Wiibm tbe above preferred group (A) and more preferred group contained therein, a more preferred group of compousds is that wherein R3 is bydrogen and R4 is alkyl, preferably mefhyl, ethyl, propyl or butyl. more preferably R4 is ethyl or propyl.(1) Wiibm tbe above preferred group (A) and more preferred is R3 and is also alkyl, preferably mefhyl, ethyl, propyl or butyl. more at R4 is ethyl or propyl.

[0086] (2) Within tbe above preferred group (A) and more preferred group contained therein, a more preferred group of compounds is that wherein RJ is alkyl, preferably methyl or ethyl and R4 is al3cyl, preferably methyl, etbyl. propyl or butyl. more preferably R4 is xnethyl. Preferably, RJ and R4 are methyl.(2) Within a preferred group, more or less methyl, ethyl and R4 are al3cyl, most methyl, etbyl. propyl or butyl. more at R4 is xnethyl. Preferably, RJ and R4 are methyl.

[0087] (3) Within the above preferred group (A) and more preferred groups contained therein, a more preferred group of compounds is that vvherein R3 and R4 together with the carbon atom to vrhich they are attacbed foim cycloalkylene, preferably cyclopropylene, cyclopentylene, or cyclohexylene, more preferably cyc3opropyīene.Cycloalkylene, cyclopropylene, cyclopentylene, cyclopentylene, cyclopentylene , or cyclohexylene, more su cyc3opropylene.

[0088] (4) Witbin the above preferred group (A) and more preferred group contained therein, a more preferred group of compounds is that wherein R3 and R4 together witih the carbon atom to vrhich they are attacbed fonu piperidin-4-yl substituted at the nitrogen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or l,l-dioxotetrahydrothiopyran-4-yl. 18 [0089] (i) Within the aboye preferred groups (A) and A(1 -4) and more preferred groups contained therein, a more preferred group of compounds is that wherein R5 is haloa]kyl, · . preferably, difluoromethyl, trifmoromethyl, 2,2,2-trifhioroethyl,1,1,2,ZA-pentailuoroeti^l, l,l,2,2,3,3,3-heptafluoropropyl andR7 andR8 are hydrogen.(4) Witbin the above preferred group (A) and more than that, but they are attacbed fonu piperidin-4-yl substituted with nitrogen, with 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl. 18 [0089] (i) Within the aboye preferred groups (A) and A (1 -4), and more preferably, R5 is haloa] Kyl, ·. preferably, difluoromethyl, trifmoromethyl, 2,2,2-trifluoroethyl, 1,1,2, ZA-pentyl-ethyl, 1,1,1,2,3,3,3,3-heptafluoropropyl and R7 andR8 are hydrogen.

[0090] (ii) Within the above preferred groups (A) and A(l-4) and more preferred groups contained therein, a more preferred group of compounds is that whersin R5 is haloa!kyl, preferably, difluoromethyl, trifIuoromethyl, 2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R7 is haloalkyl, preferably, trifluoromethvl, 2,2.2-trifluoroetiiyl, or 1, 1,2,2,2-peniafiuoroethyi, and R8 is hydrogen.(Ii) Within the above preferred groups (A) and A (l-4) and more preferred groups, there is no more than 5, halo, dif, difluoromethyl, trifluoromethyl, 2 , 2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R 7 is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl, or 1, 1,2,2,2-peniafiuoroethyl, and R 8 is also hydrogen.

[0091] (iii) Within the above preferred groups (A) and -4(1-4) and more preferred groups contained therein, a more preferred group of compounds is that wherein R6 is haIoalkyl, prsferably, dffluoromethvl, irinuoromethyĻ 2,2.2-triiluoroeihvl, or 1,1,2,2,2-pentafluoroethyĻ R' is alkvl, ņreferably, methyl, ethyl, orpropyl, andRsis hydxogen.(Iii) Within the above preferred groups (A) and -4 (1-4), more R6 is haIoalkyl, prsferably, dffluoromethvl, irinuoromethyĻ 2.2.2 -triiluorehvl, or 1,1,2,2,2-pentafluoroethyl R 'is also alkyl, preferably, methyl, ethyl, orpropyl, andRsis hydxogen.

[0092] (iv) Within the above preferred groups (A) and A(1 -4) and more preferred groups contained therein, a more preferred group of compounds is that vvherein R° is haloalķyl, preferably, oifluoromethyl, trif!uoromethyI, 2,2,2-trifIuoroethyl, or 1,1.2,2,2- 7 i ļ S · pentafluoroethyl, R is haloalkvĻ preferably, trifluoromethyi or 2,2,2-trifluoroeihyi, and R is aryl optionally substituted with one, two, or thres Re. Preferably R8 is phenyi, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-dif3uorophenyī. More preferably, R6 and R7 are trifiuorometh.yl and R8 is phenyl, 4-fiuorophenyL 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl.(Iv) Within one of the preferred groups (A) and A (1 -4), there is a haloalkyl, par, oifluoromethyl, trif! UoromethyI, 2,2,2-trifluoroethyl, or 1,1,2,2,2-7-ol pentafluoroethyl, R is haloalkyl, trifluoromethynyl or 2,2,2-trifluoroethyl, and R is aryl optionally substituted with one, two, or thres Re. Preferably R8 is phenyi, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-dif3uorophenyi. More preferably, R6 and R7 are trifluoromethyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl.

[0093] (iv) Within the above preferred groups (A) and A(1 -4) and more preferred groups contained therein, a more preferred group of compounds is that wherein R5 is haloalkyl, preferably, difluoromethyl, triiluoroiQethyl, 2,2,2-trifluoroethyl, or 1,1,2,2,3-pentafluoroethyl, R7 is aXkyl, preferably, methyl or eihyl, and R8 is aryl optionally substituted with one, tv/o, or three Re. Preferably R8 is phenyi, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl. More preferably, R6 is trifluoromethyl and R7 is methyl and R8 is phenyi, 4-fiuorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl. 19 19 LV 13669 [0094] (v) Wiihin the above prefeued groups (A) and A(l-4) and more prefeued groups contained therein, amore preferred group of compounds is that wherein Rfi is haloaIkyl, preferably, trifluoromethyl, difIuoromethyl, 2,2,2-trifluoroeihyl, or 1,1,2,2,2-peniailuoroethyb R7 is hydrogen, and R8 is aryl optionally substituted with one, two, or three Re. PxeferablyR8 is pbenyl, 4-fluorophenyl, 2.3-, 2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl. More preferably, Rs is trifluoromefhyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl, preferably 2,4-difluorophenyl.(Iv) Within the above preferred groups (A) and A (1 -4), R5 is haloalkyl, preferred, difluoromethyl, triiloyl Qethyl, 2.2 , 2-Trifluoroethyl, or 1,1,2,2,3-pentafluoroethyl, R7 is aXkyl, preferably methyl or not, and R8 is aryl optionally substituted with one, TV / o, or three Re. Preferably R 8 is phenyi, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl. More, R6 is trifluoromethyl and R7 is methyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl . 19 19 LV 13669 (v) The above prefeued groups (A) and A (l-4) and more prefixed groups contained therein, are Rho is halo, alkyl, trifluoromethyl, difluoromethyl, 2,2,2-Trifluoroethyl, or 1,1,2,2,2-pentylhydroxy R7 is hydrogen, and R8 is aryl optionally substituted with one, two, or three Re. PxeferablyR8 is pbenyl, 4-fluorophenyl, 2.3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl. More, Rs is trifluoromethyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl, preferably 2,4 -difluorophenyl.

[0095] (vi) Within the above prefeued groups (A) and A(l-4) and more preferred groups contained therein, a more preferred group of compounds is that vvherein R6 is haloalkyl, preferably, trifluromethy], 2,2,2-trifluoroeihyl, or l,l,2,2,2-pentafluoroeihyl, R7 is ha]oaIkyl, preferably, trif3uoroinethyl or 2,2,2-trifluoroefayl, and Rs is heteroaryl optionally substituted Vvith one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-y], furan-2-yl, pyridin-4-y], pyridin-3-yl, pyridin-2-yl, iinidazol-5-yĻ pyxiimdm-2-yl, pyrazin-2-yI, pyrimidin-5-yl, pyrimdin-4-yl, pyrida2r]n-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2.3ļtmadiazol-4-yl, iimdazoI-4-yl, pyrazoI-4-yl, ihiazol-2-yĻ pyrazol-4-yl, pyxrol-2-yl, pyrro]-3-y3, thiazol-4-yl, thiazol-5-y! optionailv substituted vvitii one or two metliyl.(Vi) Within the above prefeued groups (A) and A (l-4) and more preferred groups are therein a haloalkyl, preferably trifluromethy], 2.2, 2-Trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R 7 is ha] oylcyl, trifluoroethyl or 2,2,2-trifluorohexyl, and R 5 is heteroaryl optionally substituted Vvith one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl], furan-2-yl, pyridin-4-yl], pyridin-3-yl, pyridin-2 -yl, imidazol-5-ylpyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridyl] n-4-yl, isoxazol-4-yl, imidazol-2-yl yl, [1,2,3] thadiazol-4-yl, imidazo-4-yl, pyrazol-4-yl, imidazol-2-yl pyrazol-4-yl, pyriol-2-yl, pyrr] -3-y, thiazol-4 -yl, thiazol-5-y! optionailv substituted vvitii one or two methyl.

[0096] (vii) Wiihin the above preferred groups (A) and A(1 -4) aud more preferred groups contained therein, amore preferred group of compounds is that wlierein R6 is baloaIkyi, preferably, triiluromethyl, 2,2,2-trifluoroethyl, or l,l,2,2,2-pentafiuoroeihyl, R7 is alkyl, preferably, metbyl or ethyl, and and R8 is heteroaxyl optiona]ly substituted vrith one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyxidine-4-yl, pyridin-3-yl, pyiidin-2-yl, imidazol-5-yl, pyriroidin-2-yl, pyrazia-2-yl, pyriEaidin-5-yl, pyrimdinA-yl,pyAda2in-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2.3]thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazo!-4-yl, pyrrol-2-yl, pyirol-3-yl, thiaxol-4-yl, thiazol-5-yl optionally subsiituted -wiĪh one or two methyl.(Vii) The above-mentioned groups (A) and A (1 -4) are more preferred groups, there are also trioluromethyl, 2,2,2- trifluoroethyl, or 1,1,1,2,2,2-pentafluoroethyl, R 7 is alkyl, preferably methyl, and R 8 is heteroaxyl optionally substituted with one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyxidine-4-yl, pyridin-3-yl, pyridin-2-yl , imidazol-5-yl, pyrrolidin-2-yl, pyrazia-2-yl, pyridazin-5-yl, pyrimidin-1-yl, pyrazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2. 3] thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiaxol-4-yl , thiazol-5-yl optional subsiituted -white one or two methyl.

[0097] (viii) Within the above preferred groups (A) and A(1 -4) and more prefeued groups contained therein, a more preferred group of compounds is that wherein R6 is haloalkyl, preferablj, trifluromethyl, 2,2,2-tdfluoroethyl, or l,l,2,2,2-pentailuoroethyl, R7 is hydxogen, and and R8 is heteroaryl optionally substituted wi£h one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3- 20 yl, pyridin-2-yl, imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyriinidin-5-yl, pyrimdin-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2.3]thiadiazol-4-yl, irnidaxol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrdl-3-yl, tbiazol-4-yl, thia2ol-5-yl opiional]y substituted νάΐα one or two methyl. {0098] (a) Within Īhe above prefened groups (A), A(l-4), A(i-viii) and A(l-4)(i-viii), and more preferred groups contained therein, an even more preferred group of compounds is that v/herem R3 is cycloalkylaIkyl optionally substituted with one, two, or tbiee Ra independently selected Srom alkyl or balo or an Rc selected irom aralkyl or heteroaraOcyl, preferably l-meihylcyclopentylmeikyI, l-methy]cyclohexylmethyl, 1- . metnylcyclobutylmethyl, l-rnethyl-3,3-dif3uorocycIobutylrneĪhyĻ 1 -meihyl-4,4-difiuorocyclohexylmethyl, l-beimyl-cyclopropylmethyl, l-thiazol-2-ylmethylcyclopropyl3xie{hyl, or l-methyl-3,3-difiuorocyclopeniylmeihyl. {0099] (b) Within the above preferred groups (A)} A(l-4), A(l-viii) and A(i-4)(i-viii), and more preferred groups contained therein, an sven more preferred group of compounds is that VtbereinR3 is alkyl, preferably 2J2-dimethylprqpyĻ 3,3-dimethylpen.tyI, 2,2,3,3- tetrametliylbuiyl.(Viii) Within the above preferred groups (A) and A (1 -4) and more prefixed groups contained therein, R6 is haloalkyl, preferablj, trifluromethyl, 2,2,2 -tdfluoroethyl, or 1,1,1,2,2-pentylaminoethyl, R 7 is hydroxy, and and R 8 is heteroaryl optionally substituted w 1 h, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl yl, imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, \ t [1.2.3] thiadiazol-4-yl, iridazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrr-3-yl, tbiazol-4 -yl, thia2ol-5-yl] y added νάΐα one or two methyl. {0098] (a) Within a short above prefened groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii), and more rc is cycloalkylaIt is selected with one, two, or tbiee Ra and selected Srom alkyl or balo or an Rc selected aralkyl or heteroaroCyl, preferably 1-methylcyclopentylmethyl, l-methy] cyclohexylmethyl, 1 -. Methylcyclobutylmethyl, 1-methyl-3,3-difluorocyclobutylmethyl-1-methyl-4,4-difluoro-cyclohexylmethyl, 1-beimyl-cyclopropylmethyl, 1-thiazol-2-ylmethylcyclopropyl-3-yl, or 1-methyl-3,3-difluoro-cyclopenylmethyl. (B) Within the above preferred groups (A)} A (1-4), A (1-viii) and A (i-4) (i-viii), and more preferred groups contained therein, an sven more preferably 2J2-dimethylpropyl 3,3-dimethylpentyl, 2,2,3,3-tetramethylylbutyl.

[0100] (c) Within the above preferred groups (A), A(l-4), A(l-viii) and A(i-4)(i-viii), and more preferred groups contained therein, an even more preferred group of compounds is that vrkereinR3 is haloaIkyl, preferably 2,2-dicMoroethyI, 3,3,3-tdfiuoropropyl, 2,2-trifluoromethyleĪhyl, or 2,2,2-trifluoroethyl.(C) Within the above preferred groups (A), A (1-4), A (1-viii) and A (i-4) (i-viii), and more more 2,2-dichloroethyl, 2,2,3-trifluoro-propyl, 2,2-trifluoromethyl-phenyl, or 2,2,2-trifluoroethyl.

[0101] (d) Within the above preferred groups (A), A(1 -4), A(i-viii) and A(1 -4)(i-viii), and more preferred groups contained therein, an even more preferred group of compounds is tbat wberein R3 is haloa!kyl substituted with aryi, heteroaryI or heterocycloalkyl, preferably 2,2-difluoro-3-phenylpropyl, 2,2-diiluoro-3-tetrahydropyran-4-yIpropyl, 2,2-difluoro-3-moipholm-4-ylpropyl, 2,2-difluoro-3-pyridm-2-ylpropyl, 2,2-difluoro-3-pyridin-3-yipropyl, or 2,2-dichloro-3-phenylpropyL(D) Within the above preferred groups (A), A (1 -4), A (i-viii) and A (1 -4) (i-viii), and more preferred groups contained therein, an even more substituted with aryi, heteroaryl or heterocycloalkyl, 2,2-difluoro-3-phenylpropyl, 2,2-diyl chloro-3-tetrahydropyran-4-ylpropyl, 2,2- difluoro-3-moiphol-4-ylpropyl, 2,2-difluoro-3-pyrid-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylopropyl, or 2,2-dichloro-3-phenylpropyL

[0102] (e) Within the above preferred groups (A), A(l-4), A(i-viīi) and A(l-4)(i-viii), and more preferred gronps contained therein, an even more preferred group of compounds is that wherein R5 is araUcyl optionally substituted wiib one, two, or three Ra independently selected from aīkyl, haloalkyl, alhoxy, hydroxy, haloalkoxy, cyano, or balo; or optionally substituted vdth one or two Rb independently selected from bydrogen, alkyl, haloalķyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from 21 21LV 13669 hydroxyalkyl3 allcoxyaīkyl, aminoaIkyl, aiyl, heteroaiyl3 aralkyl3 heteroaralkyl, cycloalkyl3 cycloalkylaltyl, heterocycloa!3cyl, heterocycloalkyla3kyl3 acyl3 aiyloxycaxbonyl, aiallcyloxycaxbonylJ heteroaryloxycarbonyl3 heteroaralkyloxycarbonyl3 heterocyclo alkyloxycarbonylJ aryloxy, heteroaryloxy, araDcyloxy, heteroaralkyloxy3 aminocarbonyl3 aminosulfonyl3 or -SCbR11 (where R11 is alkyl3 cycloalkyl, aryl3 heteroaiyl3 or heterocycloalkyl); and furtber wberein the aromatic or alicyclic ring in R.c is optionally substituted with one3 two3 or thiee Rd independently selected from alkyl3 haloalkyI3 a!koxy, hydroxy3 haloalkoxy, orhalo.· Preferably3 R5isbenzyl3 4-methoxyben2yl3 334-dichlcrobenzyl} 2-chlorobeazyl3 4-ethoxybenzyl3 biphen-4-y3methyl, naphth-l-ylmethyī3 naphth-2-ylmethyl, 4-chlorobenzyl, 3-cblorobenzjd, 4-fluoroben2yi, 2-pheneibyl; 4-hydroxybenzyl, 2-(4-hydroxypbenyI)eihylJ 2,6-difluorobenzyl3 biphenyl-3 -yhnethyl3 3-phenyIpropyl3 or 232-dime{hyl-3-pbenylpiopyI. Prefersbly3 R3 is 2-cilorobenzyl3 3-chlorobenzyl3 or 4-iluorobenzyl.(E) Within the above preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii), and more preferred gronps contained therein, an even R5 is araUcyl optionally substituted wiib one, two, or three Ra or selected from aīkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or balo; or alternatively selected from bydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from 21 21LV 13669 hydroxyalkyl3 allcoxylayl, aminoalkyl, allyl, heteroaryl3 aralkyl3 heteroaralkyl, cycloalkyl3 cycloalkylalkyl , heterocycloa! 3cyl, heterocycloalkyla3kyl3 acyl3 aiyloxycaxbonyl, aiallcyloxycaxbonylJ heteroaryloxycarbonyl3 heteroaralkyloxycarbonyl3 heterocyclo alkyloxycarbonylJ aryloxy, heteroaryloxy, araDcyloxy, heteroaralkyloxy3 aminocarbonyl3 aminosulfonyl3 or -SCbR11 (where R11 is alkyl3 cycloalkyl, aryl3 heteroaiyl3 or heterocycloalkyl); and furtber wberein the aromatic or alicyclic ring in Rc is also selected from one3 two3 or thiee Rd is selected from alkyl3 haloalky3 ayxy, hydroxy3 haloalkoxy, orhalo. -4-y3methyl, naphth-1-ylmethyl-naphth-2-ylmethyl, 4-chlorobenzyl, 3-chlorobenzene, 4-fluorobenzyl, 2-phenyl; 4-Hydroxybenzyl, 2- (4-hydroxypbenzyl) -hydro-2,6-difluorobenzyl-3-biphenyl-3-ylmethyl-3-phenyl-propyl3 or 232-dimethyl-3-pbenzylpyridine. Prefersbly3 R3 is 2-cilorobenzyl3-3-chlorobenzyl3 or 4-ylorobenzyl.

[0103] (f) Wiihin the above prefeired groups (A), A(l-4), A(i-viii) and A(14)(i-viii), and more preferred groups contained iherein, an even more preferred group of componnds is that whereinR5 is heieroaraDcyl opiionally substituted v/itb one. two, or tbree Ra independently selected from alkyl3 haloalkyl, a!lcoxy3 bydroxy3 haloaIkoxy3 cyano3 or halo: or optionally substituted wiih one or two Rb independenily selected from bydrogen3 alkyl. haloaIkyI3 alkoxy3 hydrcxy, halca3koxy, balo, carboxy, or alkoxycarbonyl and one Rc selected from bydroxyaliyl3 a!koxyalkyl. aminoalkyl, aryl3 beteroar/l, aralkyl, heteroaiaīkyl3 cycloalkyl3 cycloaJky3aIkyl3 heterocycloallcyl3 heterocycloalkylalkyl3 acyl3 aiyloxycarbonyl3 aralkyloxycarbonyl3 heteroaiyloxycarbonyl, beteroaralkyloxycarbonyĻ aryloxy, heteroaryloxy3 araIkyloxy3 beteroaxal3cyIoxy, aminocarbonyl3 arninosulfonyl3 or -SC&gt;2RU (where R11 is aīkyl3 aiyl, heieroaryi, or heierocyc]oa]ķyi); and forther wherein tbe aromatic or alicyclic ring in Rc is optionally substituted witb one, two3 or tbree Rd independently selected from alkyl3 haloallcyl3 alkoxy, bydroxy, baloalkoxy, or halo. Preferably, Rs is 2-bromothiopben-5-ylmetbyl3 pyridin-4-ylmetbyl3 or 2,2'dimetbyl-3-pyxidin-3-ylpropyl.(F) the above prefixed groups (A), A (1-4), A (i-viii) and A (14) (i-viii), group of componnds is that jar5 is heieroaraDcyl opiionally substituted v / itb one. two, or tbree Ra and selected from alkyl3 haloalkyl, a! lcoxy3 bydroxy3 haloaIkoxy3 cyano3 or halo: or optional wiih one or two Rb independenily selected from bydrogen3 alkyl. haloaIkyI3 alkoxy3 hydrcxy, halc3cxy, balo, carboxy, or alkoxycarbonyl and one Rc selected from bydroxyaliyl3a! aminoalkyl, aryl3 beteroar / l, aralkyl, heteroaiaīkyl3 cycloalkyl3 cycloaJky3aIkyl3 heterocycloallcyl3 heterocycloalkylalkyl3 acyl3 aiyloxycarbonyl3 aralkyloxycarbonyl3 heteroaiyloxycarbonyl, beteroaralkyloxycarbonyĻ ID = heteroaryloxy3 araIkyloxy3 beteroaxal3cyIoxy, aminocarbonyl3 arninosulfonyl3 or -SC &gt; 2RU (where R11 is aīkyl3 aiyl, heieroaryi, or heierocyc] oa] Kyi); and forthera tbe aromatic or alicyclic ring in Rc is optionally substituted witb one, two3 or tbree Rd selected from alkyl3 haloallcyl3 alkoxy, bydroxy, baloalkoxy, or halo. Preferably, R 5 is 2-bromothiophen-5-ylmethyl-3-pyridin-4-ylmethyl-3 or 2,2'-dimethyl-3-pyxidin-3-ylpropyl.

[0104] (g) Within the above preferred groups (A), A(14), A(i-viii) and A(l-4)(i-viii), and more prefezred groups contained therein, an even more preferred group of componnds is that wherein R5 is -(alkylene)-S(0)2-R9 vfhere R9 is albyl, preferably R5 is methylsulfonylmethyl3 ethylsulfonylmethyĻ propyl-l-sulfonyhnethy], 2-methylpropylsulfonylmethyl3 2-methyl-sulfonylethyl3 or 2-etbylsuIfonyletbyl. 22 [0105] (h) Within the above preferred groups (A), A(l-4), A(i-viii) and A(l-4)(i-viii), and more preferred groups contained therein, an even more preferred group of coropounds is that wherein R5 is -(alkylene)-S(0)2-R9 where R9 is axyl or aralkyl opiionally substituied wi{h one, two3 or three Ra independently selected from alkyl3 haloalkyl3 alkoxy3 hydroxy3 haloalhoxy3 cyano, orhalo; or optionally substituted vAtti one ortwo Rb independently selected from hydrogen3 alkyl; haloallcyl3 alkoxy3 hydroxy, haloalkoxy3 halo, carboxy, or aHcoxycarbonyl and one Rc selected from hydroxyaīkyl3 a!koxyalkylJ anrinoa]]cyl3 aryl, heteroaryl, aralkyl3 heteroaralkyl3 cycloalkyl, cycloa]]cylallcyI3 heterocycloaliyl3 heterocycloalkylaIkyl3 acyl, aryIoxycarbonyl3 aralkyloxycarbonyl, heteroaiyloxycafbonyl. heteroaralkyloxycafbonyl3 sryloxy, heteroaryloxy, araIkyloxy, beteroaralkyloxy3 aminocafbonyl, aminosulfoīiyl3 or -S02Rn (where R11 is alkyl3 aryl. heteroaryl, or heterocycloa!kyī); and rurther wherem the aromatic or alicyclic ring in Rc is optionallv substituied with one. two, or three Rd independently selected from alkyl3 haloalkyl; aIkoxy3 hydroxy, haloalkoxy, or halo. Preferably R3 is 2-difiuorcmeihoxyphenyl-methanesulfonyImefhy], 2-phenylsulfonylethyi3 4-fluorophenyinietbanesulfonyhnethyl3 4-aniLnocarboūylphenylmethariesuhi3nylmethyĻ4-pipsra2in-l-ylpheny3mefcanesulfonyline{h3'ļ; 2-Suorophenylmethanesu!fonyīineihyl3 3-fiuorophenylme&amp;anesulfGnyhmeth.yI3 2.4.6-Īrifluorophenylmethanesulionylmeihy3, 2-, 3-, or44frfluoromethylpheny]mefcanesulionyl-meihyl3 phenylmethanesufrony]metiiyL 2-(2-3 3-3 or 4-trifluoromethylphenyl)sulfonylethyl, or 2-(2-, 3-, or 4-fiuorophenyl)sulfonylethyl.(G) Within the above preferred groups (A), A (14), A (i-viii) and A (1-4) (i-viii), more even more preferred R5 is - (alkylene) -S (O) 2-R9 vfhere R9 is also albyl, preferably R5 is methylsulfonylmethyl3 ethylsulfonylmethylpropyl-1-sulfonylmethyl], 2-methylpropylsulfonylmethyl3-2-methylsulfonylmethyl3 or 2-methylsulfonylphenyl. 22 (h) Within the above preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii), and more preferred groups contained therein, an even R5 is - (alkylene) -S (O) 2-R9 where R9 is axyl or aralkyl substituted with one or two radicals selected from alkyl3 haloalkyl-3-alkoxy3 hydroxy3 haloalhoxy3 cyano, orhalo; or alternatively vAtti one ortwo Rb is selected from hydrogen3 alkyl; haloalcyl3 alkoxy3 hydroxy, haloalkoxy3 halo, carboxy, or aHcoxycarbonyl and one Rc selected from hydroxyalkyl3axyxyalkylan anino]] cyl3 aryl, heteroaryl, aralkyl3 heteroaralkyl3cycloalkyl, cycloa]] cylallcyl3 heterocycloalkyl3 heterocycloalkylcycloalkyl acyl, aryloxycarbonyl3 aralkyloxycarbonyl, heteroarylcycloalkylcarbonyl, heteroarylcycloalkylcarbonyl, heteroarylcycloalkylcarbonyl. heteroaralkyloxycafonyl3 sylloxy, heteroaryloxy, arylcycloxy, beteroaralkyloxy3 aminocafbonyl, aminosulfonyl3 or SO2Rn (where R11 is alkyl3 aryl, heteroaryl, or heterocycloalkyl); and an aromatic or alicyclic ring in Rc is an optionallv substituted with one. two, or three Rd selected from alkyl3 haloalkyl; aIkoxy3 hydroxy, haloalkoxy, or halo. Preferably R3 is 2-difluoromethoxyphenyl-methanesulfonyImefhy], 2-phenylsulfonylethynyl-4-fluorophenyenetebenzenesulfonylmethyl3-4-fluorophenylmethylphenylmetharya-3-ylmethylphenyl-pipsrain-1-ylpheny3mefcanesulfonyline {h3'l; 2-Directhenylmethylphenylphenyl3 3-fluorophenyl &amp; anesulfGnyhmethyl. - (2-, 3-, or 4-fluorophenyl) sulfonylethyl.

[0106] (i) Within the above preferred groups (A). A(l-4). A(i-viii) and A(l-4)(i-viii)3 and more preferred groups contained therein3 an even more preferred group of componnds is that wherein R5 is -(alkylene)-S(0)2-R9 where R9 is heteroaryl or heteroaxa3]cyl optionally substituted wifh one3 wo3 or three Ra independently selected from alkyl, haloalkyl3 a!koxy, hydroxy3 haloalkoxy, cyano3 orhalo; or optionallysubstituted with one ortwo Rb independently selected from hydrogen3 alkyl, haloaliyl3 alkoxy, hydroxy3 haloa]koxy3 halo3 carboxy3 or aikoxycarbonyl and one Rc selected from hydroxyaIkyl3 alkoxyalkyl3 aminoalkyl, axyl3 heteroaryl3 aralkyļ3 heteroaralky]3 cycloaIkyl3 cycloa]]cylaIkyl3 heterocycloalkyl3 heterocycloalkylaIkyl3 acyl, aryloxycarbonyl, araūyloxycarbonyl) heteroaiyloxycafbonyL, heteroaralkyloxycarbonyl3 aiyloxy3 heteroaryloxy3 aralkyloxy3 heteroaialkyloxy, amixiocarbonyl3 aminosulfonyl3 or -S02Rn (where Ru is a]kyl3 axyl, heteroaryl3 or heterocycloalkyl);'and further wherein the aromatic or alicyclic ring in Rc is optionally substituted with one, two3 or three Rd independently selected from alkyl3 haloalkyl, alkoxy, 23 23 LV 13669 hydroxy3 haloakoxy3 or halo. Preferābly R5 is pyiidm-2-ylinethanesulfonylmethyl, pyridin-3 -yImethanesulfonylmethyl, pyiidin-4-ykaeļiianesulfony]meiiLiyl) 3-dif]uoromethoxypyridin-2-ylmethanesulfonylmetiiylJ 2-&lt;frfluoromethoxypyridm-3-ylmethmesulfonylmethyl, 4-difluoromethoxypyridin-3 -yknethanesulfonyIraethyl3 3-difiuoromeihoxypyridiū-4-ylmetfranesulfonylmethyl3 pyiiirddin-2-ylmetlianesuIfoīiyliīiethylJ pyrimidin-5-ylmeffranesulfonytaiethyl3 3drifluoromethylpyridin42-ylmethanesulfonylmefhyl3 4-trifluoromethylpyridin-3-ylmethanesulfony3methyl3 3,5-dimethylisoxazol-4-ylmethanesuīfony]raeih'yl1 2rilrmroftuan-5-y]meftanesulfonylmethyl3 2-methylihiazol-4-y]meihanesuīfonylmethyl3 fi3ian-2-yImethanesulfonylinethylJ 2-pyridio-2-ylethanesulfonylmethylJ 2-pyridin-3-yleihanesu!fonylnietiiyl&gt; 2-pyridin-4-yleihane-sulfonykneihyl5 2-pyridin-3-ylsufronyleihyl, 2-pyridin-4-yIsidfonylethyl3 3-pyridin-3-ylsulfony!propyl, l,3,5-1riazm-2-yljūaethanesulfoiiylmefliyl. 1.3,4-fhiadiazol-2-ylmethanesulfonylmethyl3 oxazol-5-ylmeihanesuliony]methyl3ihiazol-5-yliaetlian.e-sulfonylmethyl3 or tMazol42-yīmeifaanesu]fonylmeihyl.(I) Within the above preferred groups (A). A (1-4). A (i-viii) and A (1-4) (i-viii) 3 are as follows: wherein R5 is - (alkylene) -S (O) 2-R9 where R9 is heteroaryl or heteroaxa3] cyl is optionally substituted with one or more of selected alkyl, haloalkyl, coxy, hydroxy3 haloalkoxy, cyano3 orhalo; orsubstituted with one ortho Rb, selected from hydrogen3 alkyl, haloalyl3 alkoxy, hydroxy3 halo] coxy3 halo3 carboxy3 or alkoxycarbonyl and one Rc selected from hydroxyaIkyl3 alkoxyalkylaminoalkyl, axyl3 heteroaryl3 aralkyl3 heteroaralky] 3cycloalkylcyclo [] cylaIkyl3 heterocycloalkyl3 heterocycloalkylcycloalkylcycloalkyl ) heteroarylxycaflonyL, heteroaralkyloxycarbonyl3-ylyloxy3 heteroaryloxy3 aralkyloxy3 heteroalkylxy, amixocarbonyl3 aminosulfonyl3 or -SO2Rn (where Ru is a] yl3 axyl, heteroaryl or heterocycloalkyl); selected from alkyl3 haloalkyl, alkoxy, 23 23 LV 13669 hydroxy3 haloakoxy3 or halo. Preferably R5 is pyrid-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylcyanenesulfonyl] -methyl) 3-dif] fluoromethoxypyridin-2-ylmethanesulfonylmethyl] -2 &lt; tb &gt; -difiuoromeihoxypyridiū-4-ylmetfranesulfonylmethyl3 pyiiirddin-2-ylmetlianesuIfoīiyliīiethylJ pyrimidin-5-ylmeffranesulfonytaiethyl3 3drifluoromethylpyridin42-ylmethanesulfonylmefhyl3 4-trifluoromethylpyridin-3-ylmethanesulfony3methyl3 3,5-dimethylisoxazol-4-ylmethanesuīfony] raeih'yl1 2rilrmroftuan-5-yl] meftanesulfonylmethyl3 2-methylihiazol- 4-y] methanesulfonylmethyl-3-pyridin-2-ylmethanesulfonylethyl] 2-pyridio-2-ylethanesulfonylmethyl-2-pyridin-3-ylmethylphenyl &gt; 2-Pyridin-4-ylhexan-sulfonylcyclyl-2-pyridin-3-yl-sulphonyl, 2-pyridin-4-ylsulfonyl-3-pyridin-3-ylsulfonyl-propyl, 1,3,5-1-triazol-2-ylmethanesulfonylmeflyl. 1,3,4-Phiadiazol-2-ylmethanesulfonylmethyl-oxazol-5-ylmethanesulfonyl] -methyl-3-thiazol-5-ylmethyl-e-sulfonylmethyl-3-methazol-4-ylmethyl] -phenylmyl.

[0107] (j) Within. the above preferred groups (A)3 A(l-4). A(i-Yiii) and A(l-4)(i-viii), and more preferred groups contained therein. an even more prefeired group of compounds is that wherein R2 is -(alkylene)-S(0)2-R9 Tvhere R9 is heterocycloa]kyl or heierocycloa3kylaIkyI opuoiially substituted with one3 two. or tbree Rz independently selected from slkyl3 haloaI3cyī, alkoxy, hyaroxy3 ha!oalkoxy, cyano3 or balo; or opūonally substituted wnii one or iwo Rb independently selected from hydrogen3 alkyl3 haloallcyl3 slkoxy3 hydroxy. haloa]i:oxy. halo. carboxy3 or alkoxycarbonyl and one Rc selected from hydroxyalkyi3 alkoxyalkyl3 aminoaliyl3 aryl3 heteroaryl3 aralkyl3 heteroara]iyl3 cycloaHcyl3 cycloalkylaIkyl3 heierocycloaIkyl, heterocycloalkylaLk:yl3 acyl3 aiyloxycaibon'yl3 araHcyloxycarbonyl3 heiexoaryloxycarbonyi3 heieroaralkyloxycarbonyl, aiyloxy3heteroaryioxy, aralkyloxy3 beteroaralkyloxy3 aminocarbonyl3 arninosulfonyl, or -SO2R11 (where Ru is aliyl3 cycloaDcyl3 aryl3 heteroaiyl, or heterocycloalkyl); and fuither wherein the aiomatic or alicyclic ring in Rc is optionally subsiituted -with one, two3 or three Rd independently selected from alkyl3 haloalkyl3 alkoxy3 hydroxy3 haloalkoxy, orhalo. Preferably3 R5 ispiperidin-l-ylsulfony]raethyl or pipeiidin-4-ylmethaaesulfonylmethyl wherein the nitrogen atom in the piperidine ring is substituted with methyl3 ethyl3 acetyl, methylsu]fonyl, or aminosuIfonyl, tetrahydxopyran-4-ylsulfonyImetiiyl3 tetrahydropyran-4-ylsulfonylmethyl) 131 -dioxotetrahydrothiopyran-4-ylmethanesulfonylmethyl3 or morpholin-4-ylmethanesulfonyl-mefliyl. 24 [0108] (k) Within the above preferred groups (A), A(l-4), A{i-viii) and A(l-4)(i-viii)3 and more prefened groups contarned therein, an even more preferred group of compoirads is that wherein R5 is -(aIkyīene)-S'(0)2-R9 where R9 is cycloalkylalkyl3 preferably R5 is cyclopropy]xnethylsulfonylmethyl.(J) Within. the above preferred groups (A) 3A (1-4). A (i-Yiii) and A (1-4) (i-viii), and more preferred groups contained therein. more or less prefixed with a compound R2 is - (alkylene) -S (0) 2-R9 Tvhere R9 is heterocyclo] yl or heierocycloa3kylaiyu opuoiially substituted with one3 two. or tbree Rz is selected from slkyl3 haloaI3cy, alkoxy, hyaroxy3 ha! oalkoxy, cyano3 or balo; or opuonally substituted wnii one or iwo Rb is selected from hydrogen3 alkyl3 haloallcyl3 slkoxy3 hydroxy. haloa] i: oxy. halo. carboxy3 or alkoxycarbonyl and one R c selected from hydroxyalkyi3 alkoxyalkyl3 aminoaliyl3 aryl3 heteroaryl3 aralkyl3 heteroaryl] iyl3 cycloaHcyl3 cycloalkylaIkyl3 heierocycloaIkyl, heterocycloalkylaLk: yl3 acyl3 aiyloxycaibon'yl3 araHcyloxycarbonyl3 heiexoaryloxycarbonyi3 heieroaralkyloxycarbonyl, aiyloxy3heteroaryioxy, aralkyloxy3 beteroaralkyloxy3 aminocarbonyl3 arninosulfonyl, or -SO2R11 (where Ru is aliyl3 cycloaDcyl3 aryl3 heteroaiyl , or heterocycloalkyl); and fuither, or the alicyclic ring in Rc is optionally subsidized -with one, two3 or three Rd selected from alkyl3 haloalkyl 3 alkoxy3 hydroxy3 haloalkoxy, orchalo. Preferably3 R5 ispiperidin-1-ylsulfony] raethyl or piperidine-4-ylmethanesulfonylmethyl, the nitrogen atom in the piperidine ring is substituted with methyl3 ethyl3 acetyl, methylsu] phonyl, or aminosulfonyl, tetrahydroopyran-4-ylsulfonylmethyl-tetrahydropyran-4-ylsulfonylmethyl) 131 - dioxotetrahydrothiopyran-4-ylmethanesulfonylmethyl-3-morpholin-4-ylmethanesulfonyl-meflyl. 24 (k) Within the above preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii) 3 and more prefened groups contarned therein, an R5 is - (alkyene) -S '(O) 2-R9 where R9 is cycloalkylalkyl3 or R5 is cyclopropy] xylmethylsulfonylmethyl.

[0109] (1) Within the above preferred groups (A), A(1 -4), A(i-viū) and A(1 -4)(i-viii), and more preferred groups contained therein, R= is ethylsuIfonylmethyl3 2-inetlxysulfonylei]iyl3 2-methylpropylsulfonyhnethyl, benzenesulfonylmethyl3 2-phenylsulfonylethyl3 naphih-2-y]meihanesulfonyImethyl) biphenyl-2-y]methanes’aIfonyIinethy33bipheriyl-4-ylmeihanesuIionylinethyl3 pheny]methaiiesuIionyimeiiiyl3 2-pheny]methanesuIfonyle1ityi3 4-čer/Aut/lphenylmeihanesulionylmethyl, 2-fiuoro^henylmethanesulfonylmeihyl, 3- flnorophenyImethane-SĪilioriyIinethyI3 4-fluorophenylme&amp;anesulfoi'ylmsthyl3 2-cldorophenylmeflanesiilionylmeuiyl3 3-cWorophsnylmethanesulfony]inethyl3 4^Horophenylmeihanesulfoiiylnieiiiyi3 2-mētho&gt;:ypheny3meihanesu]fonyImeft!yl3 4- meihoxyphenyImeihanesuIfonyImethyl3 2-trifuoromemoxypbenyIineihaiiesulfoiiylrncĪhyl) 3- tri£3uoromethoxyphenylmeihanesuIiOiiyl-metiiy]3 4-irifiuorome&amp;cxypheny]mei3iarie-sulfonyhnethyl3 2-irifluoromethylph5nyl-meĪhanesul&amp;nylinethyl, 3 -MfluoromethyIpheny3rneihanesulfony!meĪhy3. 4- irifluorome1kylphenyime&amp;anesi!Rony3īnethy33 2-cyanbpheny3mεthaneΰlilfoτIy3metL·yL 3^yancphenyMethanesultonylineihyl 2-bromophenyImethaiLesu3foiiyIinethyI3 2-methyIpheny]meihanesuIfonyimethyL 3-methylphenyImethanesulfony3methyl3' 4-methylphenyImethanesuIfony]iQeĪhyl3 2-(4-uifluoroniethoxy-benzeīiesulfonyl)ethyl3 2-(3-trifluoromethoxybenzenesulfonyl)ethyl3 2-(24nfluoromeihoxybenzenesulfonyl)-eihyĻ 2-difiuoromeihoxypheny]methanesulfonyImethyl3 3-diRaoromethoxyphenykQethan.e-sulfony]m.ethyl3 4Aifluoromethoxyphenylmeihanesulfonylmethyl3 2-(4-difluoromethoxybenzenesulfonyl)ethyl32-(2-difluoromethoxybenzenesu]fonyl)ethyl3 2-(3-difluoromethoxybenzenesulfon.yl)ethyl3 SmMoro^Zhduorophenvlmethanesulfo^lmefl^l, 335-dimethylphenyknethanesulfony]methyl3 3,5-bis-trifluoro]iiethylphenyl-methanesulfony]methyl3 235-difiuorophenylmethanesu]fonylmethyl3 2,6-difluorophenylinethanesulfonylmethyl; 233Aifluorophenyimethanesulfonylmethyl3 3,4-difluorophenylmethanesdfony]methyl3 234-difluorophenylmethaiiesulfonyljaiethyl; 235- dichIorophenyimeihanesulfoīiylmethyl&gt; 3J4-dichIoropheny]rQethanesulfonylmethyl, 236- dichloropheny]methanesulfonylmethyl3 2-fluoro-3-methylpheny]meflmesu]fony1rnediyl) 25 25LV 13669 4-fluoro-2-1ri;fluoromethoxyphenylmethanesulfonylrnethyl3 2-fluoro'6-irifluoromefhyl-pheny3methanesulfonylmethyI3 2-:0Boro-3-1ii£luoromethylphenylmeihanesulfonyliHediyl3 2-fluoro-4-MfluoromeĪby]phenylmeftanesu]fonylmethyl3 2-f]uoro-5-trifluoromethyl-phenylmethanesulfonylmethyl3 4-fluoro-3-trifluorometbylphenylmethanesulfonylmeiliylJ 2-cMoTO-5-trifluorometbylphenyImethanesulfonyImethyl3 234,6-trifluoropheriy]iiiethane-suIfonylmethyl3 234,5-trifluorophenylmethanesulfonyliiiethyl3 233344iifiuorophenyl-methanesulfonylrnethyI3 23335-irifluorophenyImetbanesulfonylmethyl, 2,5,6-trifluoroplxenybaet]iaiiesiiIfonyl-methylI 3,4,5-(1) Within the above preferred groups (A), A (1 -4), A (i-viu) and A (1 -4) (i-viii), and more preferred groups contained therein, R = is ethylsuIfonylmethyl3 2-inethylsulfonyl] yl] 2-methylpropylsulfonylmethyl, benzenesulfonylmethyl3-phenylsulfonylethyl3 naphih-2-y] meihanesulfonymethyl) biphenyl-2-y] methanes'aIlonyIinethy33bipheriyl-4-ylmethynylethylphenyl 2-pheny] methane lphenylmeihanesulionylmethyl 2-fluoro ^ henylmethanesulfonylmeihyl, 3- flnorophenyImethane-SĪilioriyIinethyI3 4-fluorophenylme &amp; anesulfoi'ylmsthyl3 2-cldorophenylmeflanesiilionylmeuiyl3 3-cWorophsnylmethanesulfony] inethyl3 4 ^ Horophenylmeihanesulfoiiylnieiiiyi3 2-Metho &gt;: ypheny3meihanesu] fonyImeft! yl3 4- meihoxyphenyImeihanesuIfonyImethyl3 2-trifuoromemoxypbenyIineihaiiesulfoiiylrncĪhyl) 3- tri-3-fluoromethoxyphenylmeihanesuIiolylmethyl] 3 4-irifiuorome &amp; cxypheny] mei3isulfonyhnethyl3 2-irifluoromethylph5nyl-methylene sulfate &amp; nylinethyl, 3 -MfluoromethyIpheny3rneihanesulfony! MeĪhy3. 4- irifluorome1kylphenyime &amp; ANESI! Rony3īnethy33 2-yl cyanbpheny3mεthaneΰlilfoτIy3metL · 3 ^ yancphenyMethanesultonylineihyl 2-bromophenyImethaiLesu3foiiyIinethyI3 2-methyIpheny] meihanesuIfonyimethyL 3-methylphenyImethanesulfony3methyl3 '4-methylphenyImethanesuIfony] iQeĪhyl3 2- (4-uifluoroniethoxy-benzeīiesulfonyl) ethyl-3 2- (3-trifluoromethoxybenzenesulfonyl) ethyl-3 2- (24-Fluoromethoxybenzenesulfonyl) -hydryl-2-difluoromethoxypheny] methanesulfonylmethyl-3-di-trifluoromethoxyphenyl-acethane-sulfonyl] -methyl-3-fluoro-fluoro-hydroxyphenylmethyl-benzenesulfonylmethyl-2- (4-difluoromethoxy-benzenesulfonyl) -ethyl 32- (2-difluoromethoxy-benzenesulfonyl) -ethyl- (2-difluoromethoxy-benzenesulfonyl) ethyl] 2- (3-difluoromethoxybenzenesulfonyl) ethyl- (2- (3-difluoromethoxybenzenesulfonyl) ethyl) 2- (3-difluoromethoxybenzenesulphonyl) ethyl ethyl3 SmMo [beta] -hydroxy-methanesulfonyl] -1,3-dimethylphenyknethanesulfonyl] methyl3, 3,5-bis-trifluoro] -ethylphenyl-methanesulfony] methyl3,25-difluoro-phenylmethanes] -phenylmethyl-2,6-difluoro-phenylmethanesulfonylmethyl; 233Afluorophenyimethanesulfonylmethyl-3,4-difluorophenylmethanesdfony] methyl3,24-difluorophenylmethylene sulfonyl and ethyl; 235- dichorophenyimeihanesulfoylmethyl &gt; 3J4-dichioropheny] rQethanesulfonylmethyl, 236-dichloropheny] methanesulfonylmethyl3-fluoro-3-methylpheny] meflmeu] methyl] nediyl) 25LVL 13669 4-Fluoro-2-1R fluoromethoxyphenylmethanesulfonylmethyl3-2-fluoro-6-fluorofluorophenylmethylene 2methanesulfonylmethy3- -1l-fluoromethylphenylmexanesulfonylHediyl3-2-fluoro-4-fluoro-fluoro-phenyl] -phenylmethane] -phenylmethyl-3-fluoro-5-trifluoromethyl-phenylmethanesulfonylmethyl-3-fluoro-3-trifluoromethyl-phenylmethanesulfonylmethyl] -2-cyano-5-trifluoromethyl-phenylmethylsulfonyl-5-trifluoromethylphenylmethylsulfonylmethyl-234,6-trifluoro-phenylmethyl-234,6-trifluoro-methyl] -2H-trifluoro-methyl] 5-Trifluorophenylmethanesulfonylethyl-3,333,4,4-fluorophenyl-methanesulfonylmethyl-23335-irifluorophenyImetbanesulfonylmethyl, 2,5,6-trifluoro-methylene-methyl] thienylphenylmethyl-3,4,5-

trimethoxyphenylmethanesulfonylinethyl,pyiidin-2-yIiii6t3ianesu!fonyIineiliyl3pyridm-3-yImeihanesulfoxiyIinethyl3 pyridk-4-yl-meihanesulfony]methyl) 2-(pyrimn-2-ylsulfonyl)ethyl3 2-{pyridin-4-y3su]fonyl)eihyl, oxypyridin-2-ylmethanesulionylineiiiyI3 cyclohexylmerhanesulfanylmetiuyl3 cyclohexylmethanesulfonylme&amp;yI3 cyclopropylmethanesukoriylmet!iy33 • tMophene-2-suliony3metliyl3 5-cMoroūdea-2-y]insthanesuifo2iy3inethyl3 or 335-dime£hyl-isoxazo!-4-yjmeihanesulfonylmethyLtrimethoxyphenylmethanesulfonylethyl, pyridin-2-yl-pyridin-3-ylmethyl] -pyridin-3-ylmethanesulfoxylinethyl-3-pyrid-4-ylmethanesulfonyl} methyl) 2- (pyrim-2-ylsulfonyl) ethyl] 2- (pyridin-4-yl) phenyl) nonyl, oxypyridin-2-yl Methylene sulfonylsilylcyclohexylmerhanesulfanylmethyl3 cyclohexylmethanesulfonyl &amp; yl3 cyclopropylmethanesuccorylmethyl] Mophene-2-sulfonyl-3-methyl-5-cyano-formea-2-y] -phenylphenyl] -ethyl-3 or 335-dimethyl-isoxazol-4-ylmethanesulfonylmethyl]

[0110] (m) WiibiQ the above preferred groups (A)3 A(l-4), A(i-viii) and A(l-4)(i-viii). and more preferred groups coniained therein, R5 is l-ethoxycarbonylpiperidin-4-ylmetliyl31-meihylpiperidin-4-ylinethyl3 2-ieiraliydropyran-4-yleihyl3pyīioIidiii-l-ylmethyl3 piperidin-1-ylrneihyl3 raorpbolin-4-yImethyl; 2-morpho]in-4-yletbyl3 tHomorphoIm-4-ybaeihyl3 l-oxo-tinomoipholin-4-ylmethyl. l3l-dioxoi3Bomoīpholia-4-ylmeihylj tetraliydiothiopyran-4-ylmefhyl3 l-oxoĪe{rahydro{hiopyran-4-ylmeihyl3 l3l-dioxotetrahydroi}3iopyran-4-y]ineihyl31-meihylpīperazm-4-ylmeihy]3 benzyloxymeihyl3 ethoxymethyl3 isopropyloxymethyl3 2-pipeiidin-l-yl-ethyl3 2-pyiroHdin-l-ylethyl3 tert-butyloxymeihyl3 iimdazol-4-ylmeth.yl3 indol-3-y3mei!ryl3 indol-2-yknethyi3 l-beiizyl-iinidazol-4-y3metiiyI3 4-ethyI-4-methylpiperi(ūri-l' ylmethyl3 indol-l'y]methyl3 l-mefliyl-piperidm-2-ylmethyl3 2323-difluoro-3-thien-2-ylrQethyl3 or pyridin-4-ylznethyl.(M) 3b (1-4), A (i-viii) and A (1-4) (i-viii). R5 is 1-ethoxycarbonylpiperidin-4-ylmethyl-31-methylpiperidin-4-ylmethyl-3-yl-pyrrolidin-4-yl-yl-3-pyrimidin-1-ylmethyl-piperidin-1-ylmethyl] -orpholin-4-ylmethyl; 2-Morpho-in-4-ylethyl-3 H-morphol-4-yl-benzyl-1-oxo-tinomol-4-ylmethyl. 1,3-dioxol-3-ylphenol-4-ylmethyl-tetralylothiopyran-4-ylmethyl-1-oxo-bromo-pyran-4-ylmethyl-1,3-dioxotetrahydro-3-yl-pyran-4-yl] -ethyl-3-methyl-piperazin-4-ylmethyl] -3-benzyloxymethyl-ethoxymethyl-3-isopropyl-oxethyl-3-piperidine -yl-ethyl3-2-pyrrolidin-1-ylmethyl-tert-butyloxymethyl] -imidazol-4-ylmethyl-indol-3-ylmethyl-3-indol-2-ylmethyl] -1-isisyl-quinazazol-4-ylmethyl-3-ethyl-4-methylpiperidine ( η 1 -methyl-3-indol-1-yl] methyl] -1-meflyl-piperidin-2-ylmethyl-2323-difluoro-3-thien-2-yl-methyl-3-pyridin-4-ylmethyl.

[0111] (n) Within Ūie above preferred groups (A)3 A(1 -4), A(i-viii) and A(l-4)(i-viii)3 and more preferred groups coniained tberein, R5is 335-dimethyIisoxazol-4-yImefeanesulfonylmeihyi; 2-CF3metbyIplieny3iaeih.ane-suJfonyImethyI3 3-CF3pyridin-2-ylmethanesulfonylmethyl3 2-F-furan-5-ylraethanesulfonyl-iQeĪhyl32-nieĪhyl1biazol-4-ylmetbanesulfonyknethyl3 tetraLhydropyran-4-ylmethane-sulfonyImethyl31,1-άίοχο-Ιλ6-hexahydroibiopyran-4-ylmethanesu]fony]me{iiyl3 l-ethylpiperidin-4-ylmetbanesulfonyIraeth.yl3 2-oxo-tefrahydropyrimidm-4-ylmethane-sulfonylmetbyl31 -ethyl- 26 2-oxopiperidm-4-y]methaaesulfonylniethylJ 1 -acetylpiperidin-4-ylmethanesulfonylmethyl, 1 -ethoxycarbonylpiperidin^-y]meĪhanesulfony]methylJ l-meihylsulfonylpiperidin-4-ylmeiianesulfonylmeĪhyl3 l-cyclopropylpiperidm-4-ylmeiiane-sulfonylmethyl3 1-acetylazetidin-3-ylmethanesuIfonylmeihyl, l-ethoxycarbonylazeiidia-3-y]methaaesulfonylmethyl, l-methylsulfony]azeiidm-3-yiiiiethaiiesulfonyliiie{hy]J 1-ethylazetidin-3-ylniethaxLesulfonylniethyl3 l-cyclopropylazebdin-3-ylmethanesulfonylmetliyl foran-2-ylmethanesulfonylmeihyl, difluoro-(4-ili!oroplieiiyl)ineiliaiiesulfony]methylJ difluoro-(pyraziii-2-y])methanesiiIforiyIraethyl) difluoro-(2-difluoromethoxyphenyl)-methanesulfonylxnethyl, 1 -aceiylpiperidin-4-ylsiilfonylmeihyl, 1 -ethoxycaibonylpiperidm-4-ylsulfonylmeiiiyl5 l-cyclopropyllpiperidin-4-ylsulionyImethyl, 2-(pyxidin-2-yl)ei&amp;anesidionyl-methyl3 2-(pyridin-3-yl)efhaiiesulfonylmeihyl, 2-(pyridin-4-yl)eihanssulīonylmethyl, 3-(pyridin-2-yl)propariesulfoiiyliiiethyl) 2.6-diiluorophenyirneihsiiesi]Jfonyl, [1.3.5]triaxm-2-yImeihanesalfony]īneihyĻ [1.3.4]Īhiadia?;ol-2-y]methanesulfonylmethylJ oxazol-5-ylmethaQe-suIfonylineth.yi, tbiazol-5-ylmethanesulfonylmethyl5 4-fluoropbeny3methĒnesulfony]inet2iyl5 4- ajjsinocarbonylphenyIixiethanssulfonyIinethyĻ 4-piperazm-4-ylphenylD3etaaiissiilfoiiyIiDei}iy]J 5-fluoroindo3-3-yImethanesu!fonyiDietiiy3,436-difluoroindol-3-yImethanesulfonyInietiiyĻ I-m stbylindol-3 -ykaetbariesulfonylin ethyl3 4-fluoroindol-3 -ylmethsiiesiilforiykiet]iyl. 2-(5 -flTioromdol-3-yl)ethaiiesiilfonylīaEtIiyl3 2-(4.6-dnluoromdol-3-yl)ethaneSĪdfony]methyl. 2-(l-meliylindol-3-yl)ethanesTilfony]inetiiyl3 2-(4-fiuoroindol-3-yl)ethaaesulfonyIrQeihylJ 2-apiinolia-3 -ylethaiiesuhb&gt;nylīnethyl3 2-qiunolia-2-y!e1hanesbIfonylmeth.yl3 isoquinoim-3 -y3methane-sulfonykaethyl3 2-(isoqi!moIixL-3-yl)ethanesulfony]met3iyl3 2,4-difluoropyridin-3-y]methane-sulfonylmetbyl, 334-dixluoropyxidia-4-yIinsthaiiesulfonyIinethyl3 2-(2,4-diilnoropyridia-3-yl)ethanesulfonylmethyl3 2-(334-difluoropyridin-4-yl)ethaīiesīilfonyIiaetiiyl, fluoro-(234-difluoropyridin-3-yl)methanesu]fonylmei]iyl3 fluoro-(334-difluoropyiidm-4-yl)methane-suIfonylmetiyl3 234-diCF3pyridjn-3-ylmetbanesulfony]methyl3 334-diCF3pyridin- 4- ylmethane-sulfonylniethyl3 2-(234-diCF3pyridia-3-yl)ethaiiesulfonylmetIiyl3 2-(3,4-diCF3pyridin-4-yl)etbanesulfonylmethyl, jQuoro-(234-diCF3pyridin-3-yl)methauesulfony]methyl, fluoro-(3,4-diCF3pyridin-4-yl)methanesuIfonylmethyl, 4-F-pyridm-3-ylmethanesiilfoi&gt;y]ineihyl3 3-F-pyTidic-5-ylīneihaiiesulfoiiyIiQethyl32-F-pyridija-5-ylmetbanesu]fonylmetbyl, 2-F-pyridin-3-yIme1ilaxlesulfonyl·αlethyl3 5-F-pyridin-2-ylmethaiLesuIfoiiyIinethyl3 4-F-pyiidiii-2-ylmetbane-sulfony]iaediyl3 4-F-l-oxopyridia-3-ylmethaaesulfonyImethyl, 3-F-l-oxopyridin-5-y]me&amp;ane-sulfonylmethyl, 2-F-l-oxopyridin- 5- y]methanesu]fonyIioethylJ 2-F-l-oxopyiidm-3-ylmethane-sidfonyliaethyl3 5-F-l- 27 27LV13669 oxop3ddin-2-ylrnethanesulfonylmethyl3 4-F-l-oxopyridin-2-ylniethane-sulfonylmethylJ 4-CF3-pyiidin-2-ylmethanesulfoiiy]methyl, 3-CF3-pyridin-5-ylmethaiie-sulfonylmethyl33-F-pyridm-2-ylirie{haneĒulfonylmeihyl3 2-CF3-pyridin-3-y]iiie{haiie-siilfonylmethyl3 4-CF3-l-oxopyridixL-2-ylmethanesuIfoiiylmeihyl3 3-CF3-l-oxopyridin-5-yliQethanesulfonylmeihyl33-F-l-oxopyridin-2-yimethanesulfonylmeLhyl3 2-CF3-l“0xopyridin-3-ylmeihanesulfoiiyIinetfayl3 5-CF3-l-oxopyridin-2-y]ineLliaiies'alfonylineiliyl32-CH3-pyddm-6-ylinefiiaiiesulfonylmetliyl3 3-CH3-pyridm-2-yIirietlianesuIfonylmethyl3 4-CH3-pyiidin-3-ylmethmesuifonylmeĪhyl33-CH3-pyridin-4-ylmeiiiariesulfonyjtmetliylJ 2-(2-CH3-pyridiii-6-yl)e1iiaiiesTilfoiiy]inethyl32-(3-CF3-pyridia-2-yl)ethanesuifonyImethyl3 2-(4-CF3-pyridin-3-yl)eihaiiesulfonylmetlayl3 2-(3-0Ε3^^άίη-4^1)ε&amp;3ηε5η1ίοηγ&amp;αε&amp;γ13 2-C2Hj-pyridm-6-yImethaiies'iilfoiiylifleibyl3 3-C2H5-pyridm-2“ylmeihanesu]fonyimeLhyl3 4-C2H5-pyridiQ-3-y]methanesulfony]methyl3 3-C2H5-pyīidin-4-yIrQeuianesulforiyliii5{tLyl3 2-(2-C2H5-pyridin-6-yl)ethanesulfoEyljīiethyl3 2-(3-C2H5-pyiddiii-2-yl)ethariesulfonylmetliyl3 2-(4-C2H5-pyridiri-3-yl)eiJiaiiesiilfony!irie&amp;ylJ 2-(3-C2H5-pyridm-4-yl)e&amp;anesuIfonylmethyl3 2-(2-CH3-pyiidiii-3-yi)ethanesulfonyImeiliyl3 2-CF3-pyTidiQ-3-ylrQethanesulfonylxnethyl3 2-(3-CF3-pyridin-4-yl)etlianesulfoiiy3meiiiyI. 3-CF3-pyridin-4-yMethanesulfonyline1i!yl3 cimolm-3-ylmethane-sulfonylmetiiyI32-(ciimoIiīi-3-yl)eihanesulfonyImetiiyl3phtiialazin-l-ylin5thanes,alfoiiyImeĪh.yl. 2-(phiīialazin.-1 -y])sthanesulfonyimčihyļ3 2-(qidDoxalin-2-yI3&amp;thanesuuonyu3iethyi3 qumazoIiD-2-y]mefhanesulfony]iDeihy]3 2-(quinaz;Gliii-2-y])ethaiiesulfonyliiisthyĻ [l38]aaphthyxidm-2-y]ineihaiiestfibny]metliyl3 2-( [ 13 8]iiap3rŪiyiidixi-2.-yl)ethanesulfony3mefliyI3 [lJ8]naphihyiiaiii-3-ylme&amp;anesulfony]iīiethyl3 2-( [l38]naphthyxidiiL-3-yl)eihaiiesulfonylEaethyI3 3-Cl-pyridin-2-ylniethanesulforiyl[nethyl3 4-CI-pyiidin-3 -ylmethaaesulfonylmetliyl3 3-Cl-pyridia-4-ykae{hane-su]fonylxnethyl3 3-F-pyiidin-2-γ1ηιεΰΐ3ΐΐ63η1ίοιιγ1πιείίιγ13' 4-F-pyridin-3 -γΙπιεί1ΐ3ΐιε3ΐι1ίοην1^ε^13 3-F-pyiidin-4-ylmetiiaiLesulfonylinethyl3 isoq\dnolm-4-y]iīietIiaīiesuIfonyIiriethyl3 6-phenylpyiidm-2-ylm8thaiiesulfonyliaeŪiyl; 3 -phenylpyridin-2-y]m8thaiiesulforiy]iaetJiyl3 4-pheuylpyxidiii-3-y]metliaiiesulfonylnietliyl3 3-phenylpyTddm-4-y]metlūiaiLesĪilfony]meLhyl3 2-(6-phenylpyridin-2-yl)ethanesulfonylmethyl3 2-(3-phenylpyridiQ-2-yl)8Ūaaesulfonylmethyl, 2-(4-phenylpyridia'3-yl)ethanesulfonyImethyl32-(3-phenylpyxidiii-4- yl)8thajaesulfonyIinetliyl3 6-(pyridm-2-yl)pyridiih2-ylmethanesulfonylmethyl3 3-(pyridin-2-yl)pyridia-2-yIin8tliane-sulfonyliaetliyl;, 4-(ργηάίη'·2-γ1)ργπάία-3-γ]πιεώϊαε3η1β)ηγ1πιε^13 3-(pyridin-2-yl)pyiidia-4-y]methanesulfony3ineiliyl3 2-[6'(pyridm-2-yl)pyiidin-2-yl]ethaiiesĪilfonylinethyl32^[3- 28 (pyridin-2-yl)pyiidin-2-yl]etliaiiesulfonylmefhyl, 2-[4-(pyiidm-2-yl)pyridin-3-yl]ethanesulfonylmeihyl32-[3-(pyridm-2-y])pyridĪQ-4-yl]eihanesuIfonylmettiyl16-(pyridiii-3-yl)pyridin-2-yImethaiie-suIfonyIiaethyI5 3-(pyridin-3-yl)pyridm-2-yIineLhaaesulfoiiy]methyl, 4-(pyridin-3-yl)pyridi]i-3-yImetliaiiesuIfoiiylineLhyl, 3-(pyridm-3-yl)pyiidin-4-ylmethanesū]fonylmethyl3 2-[6-(pyiidin-3 -yI)pyridin-2-yl]ethax&gt;esĪilfony]iaetiiylJ 2-[3-(pyridm-3'yl)pyridm-2-yl]ethaiiesulfony]inetIiylJ 2-[4-(pyridm-3-yl)pyridin-3-yl]eili£nesulfony]rDethylJ 2-[3-(pyridin-3-yl)pyridiri-4-yl]eLhaiiesulfoiiylmeļiiyl)6-(pyridin-4-yl)pyridm-2-yImethanesiilxonyImethyl) 3-(pyridin-4-yl)pyiidiB-2-ylme1iaae3ulfonylmethyl3 4-(pyridm-4-yl)pyridin-3-ykQethanesuIforiylinethyl) 3-(pyridin-4-yl)pyddin-4-ylmethanesuIfoEylmethyl;, 2-[6-(pyriain-4-yl)pyĪidm-2-yl]-ethanssulfony]meihyl)2-[3-(pyTidin-4-yl)pyTLdin-2-yi]ei£iaQesulfonylrQethyl) 2^4-^144111-4-)4)^^4111-3-yl]eih2nesulfony]meihyl,2-[3-(pyxidin-4-yl)pyriQin-4-yl]e1i!ariesuliOEiyliiieiūyl3 2.2-dimethy]cycIopropylmeihariesukl3BylmeiitylJbiphen-2-y]rQethanesiilfoīiy]īnetliyI32-thiophen-2-ylphenylme£haiiesulfoiiyImeihyi, 2-tiuszol-2-ylphsn}^linethaBssiilfonyliii5ihyl) 2-imazol-5-ylpheny]ineĪhaBesulionylmstĪiyl) 2-[l,2.3]iMadiazol-5-ylphenylmefliane-sulfonvlmetlivl, 2-isoxazol-5-ylpheny]m5ihane5uIfo3ykaethyl. 2-(l -methylpyrazol-5-yl)phenyl-meth£assulfonyImethyl, 2-[l .2.3]iriazol-5-y]phenylmeĪliaQesulforiy3meiliylj 2-[1.2.3] oxadiazoī-5-ylpheny]meLhanesulfoiiylEDethyl3 2-[(l ,2.3)triaz-ol-5-yl]plienylmeih'aBesulfonylmethylJ 2-[(1.2.3)triazol-l-yl]pheny]meihanesulfony]methyl, oxĒSGlo[5;4-b]pyridis-2-ylmsihane-sTiIfo3iy]rQeĪhyl: oxazolo[4,5-c]pyridin-2-ylmethanesuIfonyImetfayl} oxazolo[4,5-b]pyridk-2-ylmethanesulfony]insĪh.yĻberi2imidazol-5-y]methanesulfony]īneih.yl, beiiziimdazol-4-y]iaethaiiesulioiiy]metbyl: 3ίί-πηίά3ζο[435- b] pyiidin-2-y]iBethanesulfoiiy]inethyl3 3iF-imidazo[4.5-c]py4din-2-y]methanesulfoEylffiethyl3 3-CF3-32J-imidazo[41,5-b]pyridin-2-yImet3ianesulfony]mefhyl} 3-CF3-3H-imidazo[435- c] pyiidiB-2-ylmeihanesu!fGnyImeth jd, 1-CF3- !F-iinidazo[435-c]pyridin-2-y]methanesulfonylmetiiylJ !-CF3-lif-i]iudazo[4,5-b]pyridm-2-yiiaethanesuIfony]inethyI) thiazolo[534-b]pyiidiii-2-ylmethanesulfonylmetbyl3 thiazolo[4,5-c]pyiidiii-2-ylmethaaesu]fonylDisthyi, tMazolo[4,5-b]pyiidm-2-y]methanesulfony]inethyļ, 5-CF3tinazolo[534-b]pyTidm-2-y]methanesulfonylmethyl34-CF3-thiazolo[435-c]pyridiii-2-ylmethaiies'uIfoiiy]metiiyl3 7-CF3-tbiazolo[435-b]pyridin-2-y]methaiiesujlfonylmetiiyl3 3-CF3-liī-pyTrolo[2,3-b]pyridin-2-y]me1iLanesu]foDy]]ūiethyl33-CF3-lff-pyirolo[332-c]pyridia-2-yImetbanesulfonylmeibyl, 3-CF3-ljy-pyirolo[332-b]pyridia-2-ylmethanesulfonylmethyl3 ĪDiidazo[l32-c]pyiimidia-2-methaiiesulfonyliiieibyl3 8-CF34irddazo[l32-c]pymmdm-2-methaaesiilfonyline'fliyl3 bmdazo[l32-a]pyrinūdin-2-inethaBesulfGnyImethyl3 8-CF3- 29 29 LV 13669 iirddazofl^-bjp^daziii^^linethaiiesulfonjlmethj^ljiimdazofl^-aJpjTazin^-methanesulfonylmethyl3 8-CF3-imidazo[l32-a]pyra2m-2-methanes'alfonylme{hylJ pyTazolo[l35-c]p}dinidm-2-yknethanesu3fonylraethyl3 3-CF3-pyrazolo[l35-c]pyriHŪdin-2-ylmethanesulfonylmetbyl3 4-CF3-pyrazolo[l35-c]pyriinidiii-2-yImetliaiiesulfonylmeiliyl, iiriidazo[l32-d][l&gt;2,4]triazīa-2--methariesulfonylmethyl, 3-CF3-iiiidazo[l,2-d][l)2.4]triazin-2-raethanesulfonyImethyl3 [133]benzoxazol-2-y]met3iaiiesulfoiiy3metliyl) 5-F-[l,3]benzoxazol-2-ybnethanesulfoiiyImetbyl [l33]ben2oxazol-4-yImethanesulfonylinetbyl3 2-CF3-[l33]benzoxazol-4-y]meibaiiesulfonyl-inethyI, [l33]benzoxa2»l-7-ylmethanesulfonylmeiiiyl3 2-CF3-[l33]ben2:oxazol-7-ylmethane-sulfonybnetiiyl3 [l32]benzoxazol-3-ylmetbanesiilforiy]metb.yI3 [l32]benzoxazol-4-yimethanesulfonybii5ihyi3 5-CF3-[l52]be]izoxazol-4-ylxneibaiiesiilfoiiy]iaethyl3 3-CF3-[l32jbenzoxazol4-ylmethanesulfonylmeiiiyl3 6-CF3-[l32]benzoxazol-7-y]ineihaiie-suIfony3niethyl3 6-CN-[ 1,2]be:nzoxazol-7-y3methanesidfonytoiethyl3 3-CF3-[ 132]benzoxa2;ol-7-ylmetbanesubonylmethyl3 5-F-[l32]benz;oXBzol-3-yiaaet}ianesu!foī!ylmeihyĻ [2.3]benzoxazol-7-ylm5thanesulioaylm5ibyi3 6-CF34233]bĒEZoxa2ol-7-y3Eiefbanesa]foiiy]ineihyl31-CF3-f2J3]benzoxazol-7-yImsĪbanesu]foiiy3rQsiliyl3 5-CF3-[233]beii2ox22;ol-4-ylme1iiaiie-sulfonylmetbyl3 5-CN-[233]benzoxa3oI4-ylmetiiaaes'alfony33īiethyl3 l-CF3-[233]benzoxazol-4-yimeibaGesulfonyIffieihy33 benzomiazol-2-y]me^laI!esulfonyl·πleίhyi3 5-F-benzothiazol-2-ylmeihanesulfonylme£hyl3 bēnzotbiazol^-vlme&amp;anesulfciijime^b 2-CF3-ben2X)ibiazol-4-ylmeihaiiesulfoiiy]meĪhyl3 benzotbdazoI-7-yIirieihanesu]foiiylo2eiiLyl3 2-CF3-benz-oĪhiazol-7-ylmeihaBesukonylmetīiyl3 [ 132]benzothiazoI-3-y3iiiethaiļesulfony]metbyl. [132]benzothiazol-4-ylmethanesulfony]meLbyĻ 5-CF3-[l .2]beiKothiazol-4-ylmetbanesuIfoDyIirieihyl3 3-CF3-[l32]beEZotMazoM-ylmetbanesulfonylmethyl3 6-CF3-[l32]benzothiazol-7-ybxieūiaae-sulfonyImetbyl3 6-CNT-[l32]benzo1inazol-7-ylinetiianesulfoa.yk!iethyl3 3-CF3-[l32]benzotbiazo!-7-yhiieihaiiesiiIfGGyl!īie&amp;y]3 5-F-[l )2]fceazcibiazol-3-yliaeibanesalfonylmeihyl3 [233]b8nzothiazol-7-ylmeihaiiesulfonykQethyl3 6-CF3-[2J3]benzoibiazcl-7-yIjnisthaiie-sulfony]methyl3 l-CF3-[233]benzothiazol-7-ylmeibanesulfonylmeibyl3 5-CF3-[233]beflzotMazol-4-y]methaiiesu]fonyIme£hyl, 5-CN-[2;3]beDzoihiazol-4-yImethaixesulfonylinetby]3 l-CF3-[233]benzotiiazol-4-ylmethaniesuLfonylmethyl3 4'CF3-2-CH3-tbiazoI-5-ylmetbaaesulfonyl-meĪhyl3 4-CF3-thiazol-5-y]methanesulfony]methyl3 4-CF3-2-pbeiiyl-tliiazol-5-ylmethaaesulfonylmethyl, 5-CF3-2-CH3-thiazol-4-ylmetliaaesuIfonylDietbyl3 5-CF3-thiazol-4-y]metbanesulfonylmetbyl3 5-CF3-2-phenyl-thjazol-4-y]metbanesulfonylmetbyl3 5-CH3-thiazol-2-ylraetbaaesuIfony]mettiyl3 5-CF3-tMazol-2-yImethaGesuIfoiiylmeihyl3 5-phenyl'tbdazol'2-ylmethanesiiIfonylmethyĻ 4- 30 CH3-tlu azol^^ImetiianssĪilforij^lmeĪhj-l, 4-GF3-ihiazol-2-y]iiiethaiiesulfoiiy]inethyl, 4-phenyl-thiazol-2-yliEieihaQesulfony]iaeŪiyl:, 5-CH3-2-(pyridin-2-yl)-[l3233]triazol-4-y]methanesulfonyImefliyl3 5-ΟΡ3-2-(ρ^(ίϊα-2^1)-[1&gt;2:,3]1ιΐ3ζο1-4^1ΰΐ6ΰΐ3η63υ1&amp;^]ιχΐ6^1:, 5-CF3-2-(4-methylsulfoiiylphenyl)-[ĪJ2)3]triazol-4-ylmethaiie-sulfonylmethyl3 4,5-dimethyl- [l32,4]triazol-3-ylmethanesii3forLy]riiethyl, 5-CF3-4-CH3-[l3234]triazol-3-ylmethanesulfonylmsthyl, 4-CH3-5-phenyl-[l J234]iriazol-3-ylmethaiLe~sulforLyImeihyl3 5-CF3-4-cyclopropyl-[l;234]iriazol-3-ylmeiliaxiesulfoiiylmeĪhyl; 235-dimetliyl-[l,2,4]triazol-3-ylmethanesulfonylmethyl3 5-CF3-2-CH3-[l32J4]triaz.o!-3-yIinettia2ie-sulfony]methyl) 2-CH3-5-phenyl-[l3234]triazol-3-yimethaaesulfonyĻneihyl,2-cyclqpropyl-5-pheiiyl-[l}2J4]triazol-3-ylmeihanesidfonyImetiiyl3 5-C3r3-l-CH3-[l3234]iiiasol-3-ylmeiiiaae-sulfoiiyjlinethyļ l-CH3-5-phenyl-[l3234]irisaol-3-ylmsthajie£dforiyl!Bethyl3 5-CE3-l-pli6nyl-[1.234]tda2o]-3-y]iQeūi£nesiilfony]!iiethyl3 3-CH3-[l3234]o%adiazol-5-y]methanesulfonylniethyI 3-CF3-[l3234] oxadia2oi-5-y]insihsnesii]iOTylinethyl3 3-phenyl-[1.234]oxadiaso!-5-yLD3ethane-suIfonylmeihyl3 5-CH3-[l3234]oxadia2Bl-3-ylffiethanesulfonyIīneihyI3 5-CF3-[l3234]oxadia2;o]-3-yliHeĪhaQesulfonylineihyl3 5-phenyIļlj234]oxadi£zoI-3-ymdiianesulfoiiyhnetliyl, 2-CH3- [1.3.4] cffiadi22ol-5-y3meflianesulfonylmetiiyI. 2-CF3-[ 1,3,4]cx_adiazol-5-ylir·ethane-sulfonykaeihyl. 2-phenyl-[l33,4]oxadi2zol-5-y]ffieŪianesūlionylineih.yĻ 3-CH3-[lj234]thiadia2ol-5-ylmethanesulioiiyImethyl3 3-CF3-[1.234]f!iiadiazol-5-ylmethanesulfonylineĪhyl, 3-phsnyI4132;4]tHadiazol-5-yimeihaiLčsuifoiiylmeļiiyl3 5-CH3-[lj2,4]tMadiazol-3-ylmefliaae-šulionylineĪhyl3 5-CF3-[l32.4]tbiadiazol-3-ylrnethanes'u3foriylīaeihyl, 5-phenyl-[l3234]tHadiazol-3-ylinethaiiesulfonylrQetliyl3 2-CH3- [133.4] tMadia2ol-5-ylmethanesulfonyliriethyl3 2-€F3-[1.3.4]thiadiazol-5-ylmeĪhanesdfony]iaethylJ 2-phenyl-[Ļ334]tffiadiazol-5-ylmethane-sulfonylineth.yl3 2,2-difluoropyiTolidinylmethanesulfoDylineihyl3 333-diiluoropyrrolidinyl-raethanesulfonylineth&gt;;l. 3- CF3-2/-CK3-pyrrol-2-yliueiuaiiesLilfoūylraeihyl3 3-CN-iV-CH3-pyciol-2-ylmethanesulfonylmeL!iyl34-CF3-7\LCH3-pyrrol-2-ylmetliaQesulforLyliaethyl3 4-(l-CH3-l-hydroxyethyl)-iV-CH3-pyirol-2-ylmeĪlianesulfoiiylmeth.ylJ l33-dijiieihylpyLrol-2-ylineĪhaue-sulfony]metliyl3 4-CF3-77-CH3-pyirol-3 -ylmethanesulfonylinethyl3 4-CN-iV-CH3-pyirol-3-ylmethanesulfony]xaethyl3 4-CN-ĪV-(33333-triflĪioropropyl)-pyTrol-3-ylmethanesulfonylmetiiyl3 2-CF3-2V’-CH3-pynol-3-ylmetiianesulfoDy]iQeiliyl3 2-CF3-7V-phenyl-pyirol-3-yimethane-suIfonykaethLyl3 4-CF3-pyrrol-2-ylmetlianeĒXilfonylmefhyl3 4-(l-CH3-l-hydroxyeth.yl)-pyirol-2-ylmefbiaiiesulfony]methyl3 3-CH3-pyxrol-2-ylmeth.anesulfonylmethyl3 4- CF3-pyxrol-3-ylmethane-sulfonylinetkyl3 2-CF3-pyxrol-3-y]methai&gt;esulfonylinethyl3 3-CF3-pyirol-2-ylmethane-sulfonylmetliyIJ2-CF3-pyCTol-4-ylmethaxiesulforLy]iQethyl3 2-CF3-jY-CH3- 31 31LV13669 pyirol-4-ylmethane-sulfonylmetliyl3 3-CF3-fta,-2-ylmeihanes'ulfonylmeĪhyl) 3-CN-4ur-2-ylmetFanesulfonylmethyl3 3-CF3-fux-4-y]ineihanesulfonylmethyl3 3-CN'iur-4-ylinethanesĪilfonylrQethyl3 2-CF3-fur-3-ylmethanesulfonyliDeth.yl, 3-CF3-tHazol-2-ylme{hanesulfonylmethyl, 3-CN-thiazol-2-ylmethaaesulfonylmethyl3 3-CF3-thiazol-4-ylmethaDesulfonylmethyl, 3-CN-thiazol-4-ylmethanesulfonylmeSiyl;, 2-CF3-thiazol-3 -ylmethanesulfonylmethyl, Ν-ΟΗ3-3-ΟΡ3-1H-pyrazol-5-y]methanesulfonylniethyl)7V'-CH3-3-(l-CH3-l-liydroxyetliyI)-li7-pyra2ol-5-ylmethane-sulfonylmethyl3/f-CH3-3-phenyl-l#-p)Tazol-5-y3methanesulfonylmetliyl3 yV-CH3-• 3-CF3-liī-pyrazol-4-y3i]Qe1iiaiiesiilfonylineth.yl3 JY-CH3-4-CN-lF-pyiazol-3-ylm6LhanesulIOIlylmeίiIyl37V'-pl3enyl··4-CN-li?-pyΓa^ol-3-y]IrleLh^3les'αlforlyl·πaeίhyl5Λ,'-phenyF3-CF3-liir-pyrazol-4-ylmethaiLesulfonyīmeihyĻAf-phenyl-5-CF3-liJ-pyrazol-4~ ylmethanesulfonylmethyl3 (/V'-CH3-4-CF3- lif-iinidazol-2-yl[nethaiie)-su!foiiy]inetiiyl3 [#-CH3-4-(l-CH3-l-hydroxyethyl)-lF-imidazol-2-yl}i!etiiari5]-SĪiIfonyliLisiliyl3 (N-CH3-4-phenyl- liJ-iinidflzol-2-yliaethane)-sulfonyliiieiiiyI3 N-CB.i-3 -CF3- liF-pyrazol-4-ylmefhaaes«lfonylinethyl3 (jV-CE3-2-CF3- LY-inFdazūl-5-yliaeihane)-sidfonyliūeiiiyl3 (N-CH3-2-phenyl-lF-uxdda2oI-5-y]jnethsi&gt;e)-siilfony]iīis'iliyl3 (JV-CH3-5-CF3-LIr-iiīiidazol-4-ylmethane)-Eu!fony!meihyl. (A'-pneiiyl-5-CF3-li?-iimdazol-4-ylmeihane)-sulioiiylmeīiiyl3 4-CN-[l32joxa2ol-5-yImeihanesulfonylmemyl 4-CN-3-phecy]-[l32]oxazol-5-ylmethanesulfoiiyImefiiyi3 4-CN-[l32JoxazGl-3-ylraethaaesulfoīiylīiiethy]3 4-CN-5-phenyl-[l^]oxazol-3-ylmethaiiesuIfonylrnetiiyl&gt; 4-CN-isoiMazol-5-yixaeihanes’alfonylineihyĻ 4-CN-3-phenyl-isoĪhiazol-5-ylineiliaQesulfoiiy]raeĪhyl3 4-CN-isothiazol-3-ylmethanesuIionylmethyl, 4-CN-5-ph.eiiyl-isothiazol-3-y]metliane-sulfonylineihyl:,4-CF3-[l32]oxazol-5-ylmethanesiilfonylmeth.yl34-CF3-3-CH3-[l32]oxazol-5-ylmethaīiesulfonylrQ6thyl3 4-CF3-3-pbenyl-[l32]oxa2;ol-5-ylmethanesulfonylmeliLyl3 4-CF3-[l32]oxa7Gl-3-ybaeihaaesuIfor;ylnļsthyli 4-CF3-5-CH3-[l32]oxazol-3-ylmetbanesulfonylrnethyl 4-CF3-5-phenyl-[lX|oxazol-3-ylmethanesulfonylineib.yl. 3-CF3-[l32]oxazol-4-ylmethane-sulfonylmetliylJ 5-CF3-[l32]oxazol-4-ylnietiianesulfonylxnetliyl34-CF3-[1,2]oxazol-5-ylmethaaesuIfonylmeth.yl3 4-CF3-3-CH3-[l32]oxazol-5-ylmethanesulfojaylmethylJ4-CF3-3-pheiiyl-[l:&gt;2]oxa2ol-5-y]rQeti)aiiesulfoiiylinethyl34-CF3-[l32]oxazol-3-ylmethanesulfonylmethyl;, 4-CF3-5-CH3-[l32]oxazol-3-yknetiiaiiesulfonylmethyI3 4-CF3-5-plienyl-[l32]oxazol-3-ylmethanesulfonylmethyl3 3-CF3-[l32]oxazol-4-ylmethanesulfonyImethyl3 5-CF3-[l32]oxazol-4-ylniei3ianesulforiylmeĪhyl3 4-CH3-[l,2]oxazol-5-ylmethanesulfonylme1hyl3 4-CH3-3-pibLeiiyl-[l32]oxazol-5-ylinethanesulfonylmethyl3 4-CH3-[ 132]oxazol-3 -ylmethanesulfonylmeŪiyl, 4-CH3-5-plieayl- 32 [1.2] oxazol-3-ylmethaaesiiIfony]methyl, 3-CH3-[l32]oxazol-4-ylmethane-suIfonylmethy!3 5-CHa-fl ,2] oxazol-4-ylineihanesulfoiiylrnetliyl3 4-CH3-isoiiuazol-5“yImeiiiane-suIfcnyLinethyl; 4-CH3-3'ph.enyl-isothiazol-5-ylmefhanesulfony3inethyl3 4-CH3-isothiazoI-3-ylmethanesulfony]metiiyl5 4-CH3-5-phenyl-isot4azol-3-ylme4aiies4fonylmeihyl3 3-CHs-isothiazol-4-y!inethanesulfonyltnethylJ 5-CH3-isothiaz-ol-4-y]methauesuIfony]iaetiiyl5 4-CF3- 2-CH3-[l;3]oxazol-5-ylmeihanesulfoiiy]methyl3 4-CF3-[l,3]oxazol-5-ylinethanesulionylmetiiylJ 4-CF3-2-phenyl-[lJ3]oxazol-5-y]meihanesiilfonylmethyl&gt; 5-CF3-2-CH3-il33]oxazo!-4-yl-methanesulfonyliiieLhyl3 5-CF3-[l33]oxazol-4-ylrnethaiiesulfoiiylriieLhylJ 5-CF3-2-p3ienyl-[l33]oxazol-4-ylmethaiiesulfoiiyImethyl3 5-CH3- [1.3] oxazol-2-ylmefnanesulfony]meŪiyl3 5-CF3-[!33]ox2zol-2-ylīīie4anesiikronylme&amp;yi3 5-phenyl-[lJ3]oxazol-2-yIine42ne-su]foiiybrrS&amp;yl1 4-CH3-[l33joxazol-2-ylme&amp;aiiesuuony!meihyl3 4-C3r3-[l53]oxazol-2-y]iaeiFanesuIfonyliīiethyl3 4-phsnyl- [1.3] oxazol-2-ylineļhaxiss’alfonylmeih.yi3 A4iie4yl-ir-dol-2-ylme42īiesuliony]īne4yL B-CFj-indol-2-ylme4anesulfonylrnethyI. 3-CF3-A7-methyl-indoI-2-yFiieihsnesiilfonylmeLhyl, 5-fluoro-iF-me4yi-indol-2-ylmethanesulfoiiylirLethyl.7V'-irieihyl-iiidol-3-ylmetbanesulfonyfeeibyl. 2-CF3-indol-3-yline4anes\iFonylmethyl; 2-Cf3-ĪV-meihyl-mdol-3-ylineihanesukonylinet3iyl, 5-fiuoro-iV'-meLhyl-inQol-3-y3irieihān8s4fonyliii8tIiyĻ 5-CF3-F/-methyl-mdol-4-yiiuetiianesulfonylDietiiyl3 5-CN-2V'-methyl-mdol-4-ylineĪhaae-sulfonTlmethTl, 2-Cp3-iV-me4yl-mdol-4-yIrae42nesiilfonylinetiiyl, 3-CF3-A’-meiiiyI-mdol-4-y!ineih2r!esulfoiiy3in5thyl3 6-CF3-Ar-methyl-indol-7-ylmeihanesulfonylinetiiyl3 6-CN-iV-me4yl-ir4ol-7-y3iDe4anesulfonytae4yl32-CF3-JV-rQethyI-indol-7-ylinetliaiiesulioiiylniethyl, 3-ΟΡ3-^-ιιΐ6ΰ37ΐ-]ίιιάο1-7-7Ϊτα8ί1ΐ2ηε5υί£οη7ΐΓα8ίιΐν13 Ιεηζο&amp;ΓΒη^-γ^οΙΙιβΐίβεαΙίοηγΙιιιείΙιγΙ, 3-CF3-benzof4aii-2-ylmetiiaiiesulfonyliiietFyl:, 3-CN-benzofuraa-2-y]methanesulfonylnieibyl;, 5-F-benzof4an-2-ylmetbaiiesulfony3jne{iiyl3 benzofuraa-3- ylioeibaissnlferjy3jiie&amp;y], 2-CF3-ben2»fjran-3-ylmethanesuifony3inethyl, 2-CH3-benzoxbxaa- 3- ylme4aiiesulfonylme4yl35-F-benzofuraii-3-yliiieiliaiiesi3lfoiiyliiiethyl, 5-CF3-bea2ofiEaa- 4- ylmethanesu]fonylmethyl3 5-CN-bexi2ofuxan-4-ylin.etiianesīilfonyliaetiiyl, 2-CF3-beiizoiuran-4-ylme£haiiesulfoE.y3meihyl3 3-CF3-benzofLiran-4-yIxaethanesuIfonylmeihyl3 6-CF3-benxofuran-7-ylmetbanesulfonyIrQethyl3 6-CN-benxofuran-7-y]iaethanesulfonylmethyI3 2-CF3-bexi2iofuxaii-7-ylmet3ianesiilfony3iiietliyl33-CF3-beD2oftiiaii-7-ylmetbajaesulfonyImethyl3 benzotMen-2-y]meftanesulfonylmethyl3 (3-CF3-benzotbien-2-ylmetbane)-sulfonylmeiibyl3 (3-ΟΝ4ειιζοΰπ8η'2-γ]ιη842ΐΐ8)-5ΐΟ&amp;η73ιηοί1ΐ7ΐ, (5-F-benzottaeii-2-ylmethane)-sulfonybzie4yl)bei)20iteen-3-ylme&amp;anesukonylmethyl3 (2-CF3-bejūzothien-3-ylmethaiie)-sulfony3meihyl3 (2-CH3-berizofbien-3-ylrQetliaii8)-s,ulfoiiylmetbyl) 33 33LV13669 (5dhuoro4enzothien4-ylmeihane)-sulfonyhiiethyl3 (5-CF3-benzotMen-4-y]methane)-sulfonylmethyl, (5-CN4eiizothien4-ylmeihme)-snlfonylmeihyl3 (2-CF3-benzoihien-4-ylmethane)-sulfonylmethyl3 (3-CF3-ben2othien-4'ylxneihaiie)-s'ūlfoiiy]meihyl) (6-CF3-benzothien-7-ylmethane)-sulfonylme1hyI3 (6-CN4ermothienY-ylmethane)-sulfonylmethyl3 (2-CF3-benzothien-7-yIrQeiIiane)-sulfonylmeth.yl, (3-CF3-benzothiea-7-ylmefhane)-sulfonylmethyl3 JV-methyl-benzi3nidazol-2-ylroethaiiesulfoiiylmethyl3 (5-fluoro-JVr-methyl-ben2iimdazol-2-y]methaae)-sulfonyltnethyļ (77-meihyl-indazol-3--ylmethane)-su]fonylmeihyl, (5dluoro4/mrethyldndazol4-ylmethme)-sulfonylmethyi, (2-CF3-i7-methyl-benziimdazoI-4-yIxiiefhane)-sulfoDy1iDethylJ (2-CF3dV4nethylEenziimdazoIY-y]metliaQe)-suIfonylmethyl3 (7YmeihyI^da2oM-ylmethane)-sulfonylmethyl3 (5-CF347mrethyl--mda2;ol-4-yImethane)-suIfonyLmetiiyI) (3-CF3Y/miethylHbEazoi4-ylrnethar&gt;e)-sulionylmeihyl, (6-CF3-N-mefhyl-m0azoI-7-yMe&amp;me)-sulfonylmeikyl, (6-CN44nethyl-mdazolY-yImeth£ne}-su3fonylraethy33 0r (3-CF344nethyldndaml4-ylmethane)-suEonylmetkyl. {0112] Within. the groups above, the stereochemistry ai the carbon to rvhich R5 is attached is (R) and to which R4 and R6 are atiached is (S).(N) Within the above preferred groups (A) 3 A (1 -4), A (i-viii) and A (1-4) (i-viii) 3 and more preferred groups coniained by R5is 335 -dimethyisoxazol-4-ylmethylene sulfonylmeihyi; 2-CF3methylIlien3-ene-ene-ene-3-ylmethyl-3,3-CF3-pyridin-2-ylmethanesulfonylmethyl-2-F-furan-5-yl-ethanesulfonyl-ibisyl-4-ylmethyl-1-thiazol-4-ylmethanesulfonylcarbonyl-tetraHydropyran-4-ylmethane-sulfone ] fony] methyl {1-ethylpiperidin-4-ylmetbanesulfonyl} ethyl] 2-oxo-tetrahydro-pyrimidin-4-ylmethane-sulfonylmethyl} -ethyl-26-2-oxo-piperidin-4-yl] -methanesulfonyl-ethyl} -1-acetyl-piperidin-4-ylmethanesulfonylmethyl, 1-methoxycarbonylpiperidine 1-methyl] -1-methylsulfonylpiperidin-4-ylidenesulfonylmethyl] -1-cyclopropylpiperid-4-ylidene-sulfonylmethyl] -1-acetyltetidin-3-ylmethanesulfonylmethyl-1-ethoxycarbonylmethylidene-3-yl] methanesulfonylmethyl, 1-methylsulfony] aza-3-ylmethylsulfony] azide-3-ylmethylsulfonyl] methyl] {1 H} 1-Ethyllazetidin-3-ylmethaneLesulfonylethyl 3-cyclopropyllazebdin-3-ylmethanesulfonylmethyl-foran-2-ylmethanesulfonylmethyl, difluoro- (4-yl-ethyl-ethyl) -ethylenesulfonyl] -methyl-difluoro (pyrazyl-2-y) -metha NesiiforiIlethyl) Difluoro- (2-difluoromethoxyphenyl) -methanesulfonylmethyl, 1-acetylpiperidin-4-ylsulfonylmethyl, 1-methoxycaibonylpiperid-4-ylsulfonylmethyl-5-cyclopropylpiperidin-4-ylsulfonyl, 2- (pyxidin-2-yl) &amp; anesidionyl-methyl3 - (Pyridin-3-yl) -phenylsulphonylmethyl, 2- (pyridin-4-yl) -hydsulfonylmethyl, 3- (pyridin-2-yl) -propylsulfoyl-ethyl-ethyl) 2.6-diyl-morphenenynexy] Jfonyl, [1.3.5] triaxm-2-yImeihanesalfony] [1.3.4] Ihiadia?; Ol-2-y] methanesulfonylmethyl-oxazol-5-ylmethoxy-sulfonylethyl yi, tbiazol-5-ylmethanesulfonylmethyl-4-fluoro-benzyl-3-methenesulfonyl] -ethyl-4-yl-carbonylphenyl-ethynylsulfonyl-4-piperazm-4-ylphenyl-4-piperazm-4-ylphenyl-3-piperazm-4-ylphenyl-3-methanesulfonylate; -fluoroind3-3-ymethylphenyldiethyl 3,436-difluoroindol-3-ylmethanesulfonylethylsulfanylindol-3-ylcetylsulfonyl ethyl3-fluoroindol-3-ylmethylsulfanyl]. 2- (5-Fluoro-diol-3-yl) -ethoxy-phenyl-ethyl-ethyl-2- (4,6-dichloro-dol-3-yl) -ethaneSilony] methyl. 2- (1-Melylindol-3-yl) ethanesylfil] inethyl 3 - 2- (4-fluoroindol-3-yl) ethane sulfonyl chloride 2-quinol-3-ylethynyl &gt; nylnethyl 3-qiolol-2-yl! y3methane-sulfonylacetyl 2- (isoquinolin-3-yl) ethanesulfonyl] -methyl-2,4-difluoro-pyridin-3-yl] -methanesulfonylmethyl, 334-di-fluoro-pyridid-4-yl] -isulfonyl-ethynyl-2- (2,4-diiloropyrid-3-yl) ) ethanesulfonylmethyl-2- (334-difluoro-pyridin-4-yl) -ethylenedioxy-phenyl-ethyl, fluoro (234-difluoro-pyridin-3-yl) -methaneses] -phenyl] -yl] -fluoro- (334-difluoro-pyridin-4-yl) -methanesulfonylmethyl-234-diCF3pyrid-3-yl -ylmetbanesulfonyl] methyl3,34-diCF3-pyridin-4-ylmethanesulfonyl-ethylethyl 2- (234-diCF3-pyrid-3-yl) -hexanesulfonylmethyl-2- (3,4-diCF3-pyridin-4-yl) -benzenesulfonylmethyl, -oro- (234-diCF3-pyridin-3-yl) ) methauesulfony] methyl, fluoro- (3,4-diCF3-pyridin-4-yl) methanesulfonylmethyl, 4-F-pyrid-3-ylmethanesilyl &gt; y] ethylene 3-F-pyridic-5-ynylsulfosyl-5-ylmethyl-F-pyridyl-5-ylmethylene ] fonylmetbyl, 2-F Pyridin-3-ylmethyl-xylene sulfonyl · αlethyl3-5-F-pyridin-2-ylmethyl-trifluoromethyl-4-F-pyridyl-2-ylmetbane-sulfonyl] -ediediyl-4-Fl-oxopyrid-3-ylmethylsulfonylmethyl, 3-Fl-oxopyridin-5-yl] me & ane-sulfonylmethyl, 2-Fl-oxopyridin-5-yl] methanesi] fonyIiethylJ 2-Fl-oxopyrid-3-ylmethane-sulfonylacetyl-5-Fl-27 27LV13669 oxop3ddin-2-ylmethanesulfonylmethyl3-Fl-oxopyridin-2-ylmethane -sulfonylmethyl-4-CF3-pyridin-2-ylmethanesulfonyl] methyl, 3-CF3-pyridin-5-ylmethylsulfonylmethyl-33-F-pyrid-2-yl] hexane-sulfonylmethyl-2-CF3-pyridin-3-yl] hexanylsulfonylmethyl 4-CF3-1-Oxopyridix-2-ylmethanesulfonylmethyl-3-CF3-1-oxopyridin-5-yl-acethanesulfonylmethyl-33-Fl-oxopyridin-2-ylamino-sulfonylmethyl-2-CF3-1-oxo-pyridin-3-ylmethanesulfonyl-phenyl] -5-CF3-1-oxopyridin-2-yl -y] inIlIlie'-fonylline-yl-32-CH3-pyddm-6-yl-thiophenesulfonylmethyl-3-CH3-pyrid-2-ylmethylene-sulfonylmethyl-4-CH3-pyridin-3-ylmethenesulfonyl-methyl-33-CH3-pyridin-4-ylmethylsulfonylmethylsulfonylmethylene 2 (2) -CH 3 -Pyridyl-6-yl) ethyl] phenylphenyl] inethyl 32- (3-CF 3 -pyrid-2-yl) ethanesine carbonylmethyl3 2- (4-CF 3-pyridin-3-yl) nonylsulfonylmethyl3 2- (3-0Ε3 ^^ ^ίη-4 ^ 1) ε & 3ηε5η1ίοηγ & αε &amp; γ13 2-C2Hj-Pyrid-6-ylmethylidene-phenyl-phenyl-3,3-C2H5-pyrid-2-yl] -methyl-methyl-4-C2H5-pyridazo-3-y] methanesulfony] methyl3-C2H5-pyridine -4-Chloro-enesulfonyl] - {Lyl3-2- (2-C2H5-pyridin-6-yl) ethanesulfonyl-ethyl} ethyl (2- (3-C2H5-pyridyl-2-yl) ethylsulfonylmethyl] -2- (4-C2H5-pyridyr-3-yl) n-isyl; ylJ 2- (3-C2H5-pyridm-4-yl) e-anisefonylmethyl-2- (2-CH3-pyridyl-3-yl) ethanesulfonylmethyl-2-CF3-pyridin-3-ylmethanesulfonyl-methyl-ethyl-2- (3-CF3-pyridinyl) 4-yl) etlianesulfoylmexyl. 3-CF 3 -Pyridin-4-ylmethanesulfonyl-1-yl-cimolm-3-ylmethane-sulfonylmethyl-32- (cyano-3-yl) -phenylsulfonylmethyl-3-phthalazin-1-yl] -thanes, alfoiiyImeĪh.yl. 2- (phenylazine-1-y)) sthanesulfonyimchihy3 2- (qidDoxalin-2-yI3 &amp; asesuuonyu3iethyi3 qumazoyl-2-y] mefhanesulfony] iDeihy] 3 - (quinaz; -2-y] indeneylphenyl] methyl3-2- ([13 8] iiapyridylidene-2-yl) ethanesulfony-3-methylphenyl] [1] 8-naphthynyl-3-yl &amp; anesulfony] ethyl-ethyl 2- ([l38] naphthyloxyl-3-yl) nonylsulfonyl] ethyl 3 C1-Pyridin-2-yl-ethanesulfonyl [nethyl3-4-Cl-pyridin-3-ylmethanesulfonylmethyl-3-Cl-pyridia-4-ylmethane] -phenyl] -ethyl-3-F-pyridin-2-yl] -carboxylate-3'-4-F-pyridin-3 -γΙπιεί1ΐ3ΐιε3ΐι1ίοην1 ^ ε ^ 13 3-F-pyiidin-4-ylmetiiaiLesulfonylinethyl3 isoq \ dnolm-4-yl] iīietIiaīiesuIfonyIiriethyl3 6-phenylpyiidm-2-ylm8thaiiesulfonyliaeŪiyl; 3 -phenylpyridin-2-yl] m8thaiiesulforiy] iaetJiyl3 4-pheuylpyxidiii-3-y ] methylidenesulfonylethyl-3-phenylpyTddm-4-y] methyleneLesilylphenyl] meLhyl3 2- (6-phenylpyridin-2-yl) ethanesulfonylmethyl-2- (3-phenylpyridin-2-yl) 8? 2-, 2- (4-phenylpyrid-3-yl) ethanesulfonylmethyl-32- (3-phenylpyxidyl-4-yl) 8-thiazenesulfonyl-6- (pyrid-2-yl) pyrid-2-ylmethanesulfonylmethyl-3- (pyridin-2-yl) pyrid-2-one Yi-8-liane-sulfonylacetyl ;, 4- (ργηάίη '· 2-γ1) ργπάία-3-γ] πιεώϊαε3η1β) ηγ1πιε ^ 13β- (pyridin-2-yl) pyrid-4-yl] methanesulfony-3-yl] -2- [6' (pyridyl) 2-yl) pyridin-2-yl] ethanesilylphenylethyl32- [3- (pyridin-2-yl) pyridin-2-yl] ethylidenesulfonylmephyl, 2- [4- (pyrid-2-yl) pyridin-3-yl] ethanesulfonylmethyl] - [3- (pyrid-2-y]) pyridyl-4-yl] non-propionylphenylmethyl-16- (pyridyl-3-yl) pyridin-2-ylmethylsulfonylmethyl-3- (pyridin-3-yl) pyrid-2-ylamino] sulfoyl] methyl 4- (Pyridin-3-yl) pyrid] -3-methylmethylsulfonyl-ethyl, 3- (pyrid-3-yl) pyridin-4-ylmethanesulfonyl] methylmethyl 2- [6- (pyridin-3-yl) pyridin-2-yl yl] ethax &gt; esylyl] ethylethyl 2- [3- (pyrid-3'-yl) pyridin-2-yl] ethanesulfonyl] indetyl] 2- [4- (pyrid-3-yl) pyridin-3-yl] ethyl] rDethylJ 2- [3- (Pyridin-3-yl) pyridyr-4-yl] eLhaiesulphonyl ethyl) 6- (pyridin-4-yl) pyrid-2-ylmethanesiloxylmethyl) 3- (pyridin-4-yl) pyridin-2-ylmethylene-3-sulfonylmethyl-4- (pyridin-4-yl) pyridin-3-ylmethanesulfonylethyl) 3- (pyridine -4-yl) pyddin-4-ylmethaneIfoEylmethyl ;, 2- [6- (pyridin-4-yl) pyridin-2-yl] -ethanesulfonyl] methyl) 2- [3- (pyridin-4-yl) pyTldin-2 -Yi] non-α-ionsulfonyloxyethyl) -2- (4-fluorophenyl) -4- (4) - [(4,4) -1,3-yl] n-2-sulfonyl] meiyl, 2- [3- (pyxidin-4-yl) pyriquin-4-yl] e1i ! ariesuliOEiyliiieiūyl3 2,2-dimethyl] cycIopropylmeihariesukl3BylmeiitylJbiphen-2-yl] rQethanesiilfoīiy] īnetliyI32-thiophen-2-ylphenylme £ haiiesulfoiiyImeihyi, 2-tiuszol-2-ylphsn} ^ linethaBssiilfonyliii5ihyl) 2 imazol-5-ylpheny] ineĪhaBesulionylmstĪiyl) 2- [l, 2.3] iMadiazol-5-ylphenylmefliane-sulfonylmethyl], 2-isoxazol-5-ylpheny] m5hane5uIfo3ykaethyl. 2- (1-Methylpyrazol-5-yl) phenyl-methanesulfonylmethyl, 2- [1,2,3] iriazol-5-y] phenylmethyl-qesulfori-3-yl] -2- [1.2.3] oxadiazole-5-ylpheny] meLhanesulfoylEDethyl3 2 - [(l , 2.3) triazol-5-yl] pentylmethyl-benzenesulfonylmethyl-2 - [(1.2.3) triazol-1-yl] phenylethanone] methyl, oxoGlo [5; 4-b] pyrid-2-ylmethane-sTiIf3iy] rQeyl: oxazolo [4,5-c] pyridin-2-ylmethanesulfonylmethylphenyl} oxazolo [4,5-b] pyrid-2-ylmethanesulfony] insylic acid 2-imidazol-5-yl] methanesulfony] -cyclohexylbenzimidazol-4-y] iaethaiiesulioiiy] metbyl: 3ίί-πηίά3ζο [435-b] pyridin-2-yl] -Bethanesulfoyl] -ethyl-3β-imidazo [4.5-c] pyridin-2-y] methanesulfo-ethyl-ethyl-3-CF3-32J-imidazo [41,5-b] Pyridin-2-ylmethylanesulfonyl] -phenyl} -3-CF3-3H-imidazo [435-c] pyridin-2-yl] -methylmethyl, 1-CF3-F-quinodazo [435-c] pyridin-2-y] methanesulfonylmethyl] yl! -CF3-Lif] iudazo [4,5-b] pyrid-2-ylmethanesulfonyl] -ethyl) thiazolo [534-b] pyridyl-2-ylmethanesulfonylmethyl-3-thiazolo [4,5-c] pyridyl-2-ylmethane] Mazolo [4,5-b] p yid-2-y] methanesulfony] inethyl, 5-CF3-thiazolo [534-b] pyrid-2-yl] methanesulfonylmethyl-34-CF3-thiazolo [435-c] pyridyl-2-ylmethylidene] methyl] -7-CF3-tbiazole [435] -b] pyridin-2-yl] methanesulfonylmethyl-3,3-CF3-yl-pyrrolo [2,3-b] pyridin-2-yl] methyl] -phenyl]] ethyl-33-CF3-1H-pyrrolo [332-c] pyridine-2 -methylbenzenesulfonyl-methyl, 3-CF3-yl-pyrrolo [332-b] pyrid-2-ylmethanesulfonylmethyl-3H-imidazo [1232-c] pyrimid-2-methanesulfonyl-ethyl] -8-CF34-transdiazo [1332-c] pymmdm-2-methanesulfonyl-phenyl] bmdazo [l32- a] Pyrimidine-2-inethoxyBesulfGnyImethyl3-CF3- 29 29 13139 Iirddazof1- [beta] -disil-2-ylmethane sulfonylmethyl] -imidazol-1-yl] thiazine-4-methanesulfonylmethyl-8-CF3-imidazo [l32-a] pyra-2-methanes'alfonylme { chylpyrazol [1,335-c] p-dinid-2-ene-3-ylmethyl-3,3-CF3-pyrazolo [1,3-c] pyrrolidine-2-ylmethanesulfonylmethyl] -4-CF3-pyrazolo [1,3-c] pyridinyl-2-ylmethylsulfonylmethyl, iiridazo [l32-d] ] [l &gt; 2,4] triazole-2-methariesulfonylmethyl, 3-CF 3 -ididazo [1,2-d] [1] 2.4] triazine-2-raethan esulfonymethyl3 [133] benzoxazol-2-yl] methylenedioxy-3-methyl) 5-F- [1,3] benzoxazol-2-ynnethanesulfonylmethyl- [1,333] benzoxazol-4-ylmethanesulfonyl-methyl-2-CF3- [1,3] benzoxazol-4-yl] -benzoxazol-4-yl} -methoxysulfanyl-ethyl] -ethylsulfanyl-ethyl] -ethylsulfanyl-ethyl] -ethylsulfanyl-ethyl] -hexylsulfanyl-ethyl] , [1333] benzoxa2,1-7-ylmethanesulfonylmethyl3,2-CF3- [1,333] benz2: oxazol-7-ylmethanesulfonylmethyl] [1332] benzoxazol-3-ylmethylenediamilyl] methyl] [1332] benzoxazol-4-ylmethanesulfonyl-5H-3-CF3 [l52] be] isoxazol-4-ylxenibaisilylphenyl] -ethyl-3,3-CF3- [12β-benzoxazol-4-ylmethanesulfonylmethyl] -6-CF3- [1332] benzoxazol-7-yl] imidazinyl} -ethyl] -6-CN- [1,2] nzoxazole- 7-y3methanesidylphenethyl 3-CF3- [132] benzoxa2; ol-7-ylmetbanesubonylmethyl3-5-F- [l32] benz; -7-Y3Eiefbanes] foil] ineyl31-CF3-f2J3] benzoxazol-7-ylamino] -phenyl] -silylsilyl 5-CF3- [233] imidazol-2-ol; CF3- [233] benzoxazol-4-yimeiGesulfonyIff benzo-thiazol-2-yl] methylsulfanyl-5-fluoro-benzothiazol-2-ylmethanesulfonylmethyl-benzenesulfonyl-4-fluoro-benzo [b] 2-CF3-benzo [b] iiazol-4-ylmethylsulfoyl] -methyl-benzothiazol-1-one yiirieihanesi] foiiylo2eiLyl3 2-CF3-benz-oylhiazol-7-ylmethylBesuconylmethyl-3 [132] benzothiazo-3-ylethylsulfony] methyl. [132] benzothiazol-4-ylmethanesulfony] MeLbyL 5-CF3- [1,2] bei Kothiazol-4-ylmetbaneneIdioxyuryl-3-CF3- [1,3] beezotazoM-ylmetbanesulfonylmethyl3-6-CF3- [13] benzothiazol-7-yloxy] sulfonylmethyl-6- CNT- [l32] benzoazol-7-yl-ethanesulfonylcyclohexyl-3-CF3- [1,332] benzothiazol-7-yl-thienyl] -Glycyl & y] 3 5-F- [1) 2] -ceacibiazol-3-ylbenzenesulfonylmethyl] [233] b8nothiazol-7-ylmethylsulfonylcyclyl-6-CF3- [2J3] benzo-benzyl-7-yl] thienylsulfonyl] methyl3-CF3- [233] benzothiazol-7-ylmeibanesulfonylmybyl3-5-CF3- [233] trifluoro-4-y] methaiiesu] 5'-CN- [2; 3] beDiazhiazol-4-ylmethoxy-sulfonylmethyl] -3'-CF3- [233] benzothiazol-4-ylmethyl-4-fluorophenyl-4'-CF3-2-CH3-thiazol-5-ylmethylate sulfonylmethyl-4-CF3-thiazole -5-y] methanesulfony] methyl3 4-CF3-2-p-ethyl-thiazol-5-ylmethylsulphonylmethyl, 5-CF3-2-CH3-thiazol-4-ylmethylene-1-phenyl-diethyl-5-CF3-thiazol-4-yl] -methanesulfonylmethyl-5-CF3- 2-Phenyl-thiazol-4-yl] -metbanesulfonylmethyl-5-CH3-thiazol-2-yl-bromoate; 3,5-CF 3 -Mazol-2-ylmethylglypholylmethyl-5-phenyl'-bdazol-2-ylmethanesulfonylmethyl-4-CH3-trifluoro-azimidin-2-ylmethyl-4-yl] -methyl-1, 4-GF3-ihiazol-2-yl] -ethylsulfoyl] -ethyl, 4- phenyl-thiazol-2-yl-ethylhexylsulfony] iaeyl :, 5-CH3-2- (pyridin-2-yl) - [133233] triazol-4-y] methanesulfonyImeflyl3 5-ΟΡ3-2- (ρ ^ (ίϊα-2 ^ 1) ) - [1 &gt; 2:, 3] 1ιΐ3ζο1-4 ^ 1ΰΐ6ΰΐ3η63υ1 & ^] ιχΐ6 ^ 1 :, 5-CF3-2- (4-methylsulfoylphenyl) - [(2S) 3] triazol-4-ylmethylsulfonylmethyl3 4.5 -dimethyl- [1,2,4] triazol-3-ylmethanesilyl] -pyridyl, 5-CF 3 -4-CH 3 - [1 3234] triazol-3-ylmethanesulfonylmethyl, 4-CH 3 -5-phenyl- [1 J 234] iriazol-3-ylmethyl sulfonylmethyl-5-CF 3 -4-cyclopropyl- [1; 234] iriazol-3-ylmethylxysulfoylmethyl; 235-Dimethyl- [1,2,4] triazol-3-ylmethanesulfonylmethyl3-5-CF3-2-CH3- [1332] triazol-3-ynethylsulfony] methyl) 2-CH3-5-phenyl- [l3234 ] triazol-3-yimethylsulfonyl-enylcyl, 2-cycl-propyl-5-pheyl- [1] -2J4] triazol-3-ylmethane-diphenylmethyl-5-C3r3-1-CH3- [133234] diazol-3-ylmethylene-sulfoylsulfanyl-1-CH3-5-phenyl - [133234] irisol-3-ylmethyl-phenylmethyl-5-CE3-1-yl] -1- [1,234] dio] -3-y] indole-4-yl] ethyl] -3-CH3- [1,334] o% adiazol-5 y] methanesulfonyl ethynyl 3-CF3- [133234] oxadiazol-5-yl] hexenyl] iothylethyl-3-phenyl- [1,234] oxadiazol-5-yl] -ethane-sulfonylmethyl-5-CH3- [133234] oxadia-2Bl-3-ylfluoroethylsulfanyl-5-CF3- [133234] oxadia2; o] -3-ylhydroxysulfonyl-5-phenyl] -234] oxadate-3-ene-ene-sulfonylmethyl-ethyl, 2-CH3- [1.3.4] cfiadi22ol-5-y3meflianesulfonylmethyl. 2-CF 3 - [1,3,4] cis-adiazol-5-yl] ethane-sulfonykaeihyl. 2-phenyl- [1,3,4] oxadiazol-5-yl] pyridinylmethyl-3-CH3- [1,2,2] thiadiazol-5-ylmethanesulfonylmethyl-3-CF3- [1,234] thiadiazol-5-ylmethanesulfonyl] -yl, 3-phsnyl4132; ] Hadiazol-5-yimeihydroxyphenylmethyl-3 5-CH3- [11,2,4] -Madiazol-3-ylmethyl-sulfonyl-ethyl] -5-CF3- [1232.4] tbiadiazol-3-ylmethylene-3-yl] ethylene, 5-phenyl- [1,334] Hadiazol-3- overethane sulfonylquetyl 3 2-CH 3 - [133.4] Madia 2 -ol-5-ylmethanesulfonyl-ethyl-ethyl 2- [F 3 - [1.3.4] thiadiazol-5-ylmethanesulfonyl] -acetyl-2-phenyl- [334] thiadiazol-5-ylmethane-sulfonyl-ethyl. difluoro-pyrrolidinylmethanesulfo-dynyl-3,333-diiloropyrrolidinyl-raethanesulfonylethylene &lt; / RTI &gt; 3-CF3-2 / -CK 3 -Pyrrol-2-ylideneLilofluoroethyl3,3-CN-N-CH3-pycol-2-ylmethanesulfonylmethyl-4-CF3-7 LCH3-pyrrol-2-ylmethylsulfamyl-ethylethyl 4- (1-CH3-l- hydroxyethyl) - N-CH 3 -pyrrole-2-ylidenesulfonylmethyl] -1,3-di-dihydro-pyrrol-2-ylamino-sulfonyl] -methyl-3-CF 3 -77-CH 3 -pyrrol-3-ylmethanesulfonyl-ethyl-4-CN-N-CH 3 -pyrrole-3 ylmethanesulfony] xaethyl3 4-CN-N- (33333-trifluoropropyl) -pyrrol-3-ylmethanesulfonylmethyl3,2-CF3-2V'-CH3-pynol-3-ylmethanesulpho-d]] ethyl] -2-CF3-N-phenyl-pyrrole-3-ylmethanone Sufonycethyl3 4-CF 3 -Pyrrol-2-ylmethylenedioxyphenylmethyl-4- (1-CH3-1-hydroxyethyl) -pyrrol-2-ylmethylsulfony] methyl3-3-CH 3 -pyrrol-2-ylmethanesulfonylmethyl-4-CF 3 -pyrrol-3-yl ylmethane-sulfonylmethyl-2-CF 3 -pyrrol-3-yl] methane &lt; / RTI &gt; -ylmethane-sulfonylmethyl-3-CF3-fta, -2-ylmethanesulfonylmethyl) 3-CN-4ur-2-ylmethanesulfonylmethyl3 3- CF3-Fux-4-y] Inanhanesulfonylmethyl-3-CN-urur-4-ylmethyl-phenylphenyl-2H-CF3-fur-3-ylmethanesulfonyl-Dethyl-3-CF3-Hazol-2-ylmethanesulfonylmethyl, 3-CN-thiazol-2-yl ylmethaneesulfonylmethyl3-CF3-thiazol-4-ylmethesulfonylmethyl, 3-CN-thiazol-4-ylmethanesulfonylmethyl ;, 2-CF3-thiazol-3-ylmethanesulfonylmethyl, Ν-ΟΗ3-3-ΟΡ3-1H-pyrazol-5-y] methanesulfonylmethyl) 7V'-CH3-3- (1-CH3-1-Lydroxyethyl) -1'-pyrazol-5-ylmethane-sulfonylmethyl3- (CH3-3-phenyl-1 # -p) Tazol-5-ylmethanesulfonylmethyl3 Y-CH3- • 3-CF3-Li-pyrazol-4-yl] QeI-eneylphenylethyl-3YY-CH3-4-CN-1F-pyiazol-3-ylmethyl-1'-ylmethyl-1H-pyridin-4-yl-pyrimidin-3-yl] IrleLh ^ 3les'αlforlyl · πaeίhyl5Λ, '- phenyF3-CF3-lir-pyrazol-4-ylmethyl-lysulfonylhydryl-phenyl-5-CF3-1H-pyrazol-4-ylmethanesulfonylmethyl (N-CH3-4-CF3-lifinidazole) 2-yl [Nethydrous] phenyl] inethyl3 [# -CH3-4- (1-CH3-1-hydroxyethyl) -1F-imidazol-2-yl] ethyl} -5] -IlonylLysilyl3 (N-CH3-4- phenyl-li-iinidflzol-2-ylmethane) sulfate Nyll3I-N-CB1-3-CF3-FF-pyrazol-4-ylmethylphenylethyl3 (N-CE3-2-CF3-LY-inFdazul-5-ylhyde) -sulfonylidenyl3 (N-CH3-2-phenyl-1F- uxdda2o-5-y] jnethsi &gt; e) -Silfony] Iisilyl3 (JV-CH3-5-CF3-Li-iiididazol-4-ylmethane) -Eu! (A'-Pylyl-5-CF3-ylimidazol-4-ylmethane) -sulfanylmethyl-4-CN- [12β] oxazol-5-ylmethanesulfonylmethyl-CN-3-phecy] - [1332] oxazol-5-ylmethanesulfonyl] -4 CN- [1232] OxazGl-3-yl-ethylsulfoyl-ethyl-ethyl] -4-CN-5-phenyl- [1 H] oxazol-3-ylmethyl-methyl-methyl &gt; 4-CN-Isolazol-5-ylethane-naphthalene-4-CN-3-phenyl-iso-thiazol-5-ynyl-quesulfoyl] -ethyl] -4-CN-isothiazol-3-ylmethylion-1-ylmethyl, 4-CN-5-phenyl-isothiazol-3-one y] Methylene sulfonylhydryl, 4-CF 3 - [1332] oxazol-5-ylmethanesilfonylmethyl-34-CF 3 -3-CH 3 - [13]] oxazol-5-ylmethynylsulfonylthio-3-CF 3 -3-pbenyl [13] oxa2; -5-ylmethanesulfonylmethyl-yl3-CF3- [1332] oxa7Gl-3-ybaeylamino] -propyl 4-CF3-5-CH3- [1332] oxazol-3-ylmethanesulfonylmethyl 4-CF3-5-phenyl- [1X-oxazol-3-ylmethanesulfonyl] .yl. 3-CF3- [1332] oxazol-4-ylmethanane-sulfonylmethyl] -5-CF3- [1332] oxazol-4-yl-ethanesulfonyl-methyl-34-CF3- [1,2] oxazol-5-ylmethyl] -phenylmethyl-4-CF3-3-CH3- [ 122.] oxazol-5-ylmethanesulfoylmethyl-4-CF3-3-pheyl- [1: &gt; 2] oxaol-5-yl] acetylsulfonylethyl-34-CF3- [1,3] oxazol-3-ylmethanesulfonylmethyl; 4-CF3-5-CH3 - [1332] oxazol-3-ylethynylsulfonylmethyl-4-CF3-5-pienyl- [1332] oxazol-3-ylmethanesulfonylmethyl-3-CF3- [1332] oxazol-4-ylmethanesulfonylmethyl3-5-CF3- [1,3] oxazol-4-ylidenesulfonylmethyl] -4 -CH3- [1,2] oxazol-5-ylmethanesulfonylmethyl-4-CH3-3-pibyl-ethyl [13] oxazol-5-ylmethanesulfonylmethyl-4-CH3- [132] oxazol-3-ylmethanesulfonylmethyl, 4-CH3-5-leadyl 32 [1.2] oxazol-3-ylmethane sulfonyl] methyl, 3-CH3- [1332] oxazol-4-ylmethanesulfonylmethyl-5-CHa-fl, 2] oxazol-4-ynylcanesulfonylmethyl] -4-CH3-isolazole-5 " -suIfcnyLinethyl; 4-CH3-3'-Phenyl-isothiazol-5-ylmethanesulfonyl-3-methyl-4-CH3-isothiazo-3-ylmethanesulfonyl] -methyl-5-CH3-5-phenyl-isothiazol-3-ylmethyl-4-phenylmethyl-3-CH-isothiazol-4-ylmethylsulfonylmethyl ester 5-CH3-isothiazol-4-yl] methanesulfonyl] acetyl-4-CF3-2-CH3- [1,3] oxazol-5-ylmethanesulfonyl] methyl3-CF3- [1,3] oxazol-5-ylmethanesulfonylmethyl 4 -CF3-2-phenyl- [1] 3-oxazol-5-yl] methanesulfonylmethyl &gt; 5-CF3-2-CH3-yl33] oxazol-4-ylmethanesulfonyl] alkyl-5-CF3- [1,333] oxazol-4-ylmethylsulfoyl] ethyl 5-CF3-2-p3-phenyl- [1,333] oxazol-4-ylmethylsulfoylmethyl-3-CH3- [1.3] Oxazol-2-ylmethanesulfonyl] Meyl3-5-CF3 - [33] ox2zol-2-yl] azanedronone &amp; yi 5,5-phenyl- [1] 3-oxazol-2-yn-ene-4-yl] -phenyl bromide &lt; / RTI &gt; 2-yuan &amp; novel meiyl3 4-C3r3- [153] oxazol-2-y] ene-phenyl-ethylidene-4-phsnyl- [1.3] oxazol-2-yl-hexane-alpha-4-yl-4-yl-2-ylmethylene] CFI-indol-2-ylmethylsulfonylmethyl. 3-CF3-A7-methyl-indol-2-yl-thienylphenylmethyl-5-fluoro-1F-methyl-indol-2-ylmethanesulfonyl] -ethyl-7H-enynyl-iiidol-3-ylmethanesulfonylphenyl. 2-CF 3 -indol-3-yl-4-fluoronylmethyl; 2-C3-N-N-methyl-molol-3-yl-cyano-carbonyl-3-yl-5'-fluoro-N'-methyl-benzol-3-ylmethane-8-carbonyl-5-CF3-F-methyl-mol-4-yl-ethanesulfonyl-diethyl-3-CN-2V'-methyl -dol-4-ynylacetylsulfonylmethylTol, 2-C3-N-methylmol-4-yl-ene-2-ylmethyl-ethyl, 3-CF3-N'-methyl-molol-4-ylmethyl] -methylsulfanyl-5-yl-6-CF3-Ar-methyl-indole -7-cyano-sulfonyl-ethynyl-6-CN-N-methyl-4-ol-7? -γ ^ οΙΙιβΐίβεαΙίοηγΙιιιείΙιγΙ, 3-CF3-Benzof4aii-2-ylmethylsulfonyl-ethyl-phenyl: 3-CN-benzofuraa-2-y] methanesulfonylidenibyl; -CF 3 -Benzo 2 -phen-3-ylmethanesonylphenyl 3 -ethyl, 2-CH 3 -benzoxybiphen-3-ylmethylsulfonylmethyl-35-F-benzofurai-3-yl] thienyl 3-trifluoromethyl, 5-CF 3 -beafophen-4-ylmethyl] phonylmethyl] T-butyl 5-CN-oxy-2-fluoro-4-yl] -ethianesilyl-phenylacetyl, 2-CF 3 -isisol-uran-4-ylmethylsulfo-3-methyl-3-CF 3 -benzofliran-4-ylmethanesulfonylmethyl-6-CF 3 -benxofuran-7-ylmethanesulfonyl} -ethyl-6-CN-benzoxofuran-6-CN-benxofuran- 7-y] -ethanesulfonylmethyl-3-CF3-butyloxy-2-ylmethyl-3-ene-3-yl-phenyl-3-ethyl-33-CF3-beta-thiophenyl-7-ylmethyl-sulphonylmethyl-benzothi-2-yl] -methanesulfonylmethyl- (3-CF3-benzothien-2-ylmetbane) -sulfonyl-methyl-3-sulfonylmethyl-3 (β-4? ] ιη842ΐΐ8) -5ΐΟ &amp; η73ιηοί1ΐ7ΐ, (5-F-Benzoethoxy-2-ylmethane) -sulfonylidene))) 20-ene-3-yl &amp; anesuconylmethyl3 (2-CF3-beuzothien-3-ylmethane) sulfonylmexyl (2-CH3-bisofen-bis) 3-yl-trifluoro [8] -sylphenylmethyl) 33 33LV13669 (5-fluoro-benzothien-4-ylmethane) -sulfonyl-ethyl (5-CF3-benzothi-4-yl) -methanone-sulfonylmethyl, (5-CN4-enisothien-4-yl) -carbonylmethyl-3 (2-CF3-benzoic acids) 4-ylmethane) -sulfonylmethyl3 (3-CF3-benzothien-4'-ylnexy) -sulphoyl] methyl) (6-CF3-benzothien-7-ylmethan) sulfonylmethyl (6-CN4ermothienY- ylmethane) -sulfonylmethyl3 (2-CF3-benzothien-7-ylidene) -sulfonylmethyl, (3-CF3-benzothi-7-ylmethane) -sulfonylmethyl-3H-methyl-benzylidenzol-2-yl-ethanesulfonylmethyl-3 (5-fluoro-JVr-methyl) benzimidazol-2-yl] methaae) sulfonylmethyl (77-methyl-indazol-3-ylmethane) -phenylmethyl, (5dluoro4 / mrethyldndazol4-ylmethyl) sulfonylmethy, (2-CF3-i7-methyl-benzimidazo-4) -yloxyhane) sulphoDy1DethylJ (2-CF3dV4nethylEenzimidazoyl-y] methylQe) sulfonylmethyl (7Ymehydryl 2 -methylmethane) -sulfonylmethyl3 (5-CF347mrethyl - mda2; ol-4-yImethane) -suIfonyLmetiiyI) (3-CF 3 Y / H ; e) -Sulionylmihyl, (6-CF3-N-mefhylmol-I-7-Me &amp; Me) -sulfonylacyl, (6-CN44neth-mdazolY-yImeth £ ne} -su3fonylethyl33r (3-CF344nethyldndaml-ylmethane) -suEonylmethyl. {0112] Within. and R6 is attached to (R) and to which R4 and R6 are atiached (S).

[0113] Within the groups above, the stereochemisiry at ihe carbon to which R5 and R6 are attached is (R) and to -vvhich R4 is attached is (3).R5 and R6 are attached (R) and -vvhich R4 is attached (3).

[0114] (B) Another preferred group of compounds of Formula (T) is that vrherein: R3 is alkyi3 preferably methyl or eihyl and R4 is alkyl3 preferably methyl, ethyl, propyl or butvl, more preferablv R4 is methyl. Preferably, R3 and R4 are methyl, [0115] (C) Yet another preferred group of compounds of Formula (I) is that wherein R3 and R4 together rvith the carbon atom to which they are attached form cycIoalkylene3 preferably cyclopropylene, cyclopentyīene, or cyclobexylene, more preferably cyclopro.pylene.(B) Another preferred compound of Formula (T) is that R3 is alkyl or methyl and is also alkyl, ethyl, propyl or butyl, more preferred R4 is methyl. Preferably, R3 and R4 are methyl, (C) Yet another preferred compound of Formula (I) R3 is R4 cyclropylene, cyclopropylene, or cyclobexylene. , more at cyclopro.pylene.

[0116] (D) Y et another pieferred group of compounds of Formula (Γ) is that rvherein R3 and R4 together with the carbon atom to which they are atiached form piperidin-4-yl substituted at the nitrogen atom with ethyl, 2,2,2-triiluoroethyl or cyclopropyl, tetrahyaropyran-4-yl, tetrahydrothiopyran-4-yl, or l,l-(hoxotebah.ydrothiopyran-4-y].(D) Y and another group of compounds of Formula () is that rvhere together with the carbon atom which is atiached form piperidin-4-yl at the nitrogen atom with ethyl, 2, 2,2-trifluoroethyl or cyclopropyl, tetrahydrofuran-4-yl, tetrahydrothiopyran-4-yl, or 1,1'- (hoxotebah.hydrothiopyran-4-y).

[0117] (E) Yet another preferred group of compounds of Formula (I) is that wherein Rs is haloaIķyl3 preferably3 difluoromethyl, trifluoromethyl, 23232hrifluoroethyl3 or 13132,232-pentafluoroethyl andR7 and R8 are hydrogen. 34 [0118] (F) Yet anotber preferred group of compounds of Formula (I) is that v/berein R6 is haloaUcyl, preferably, diiluoromethyl, trifluoromettr/l, 2,2,2-triiluoroetbyl, ot 1,1,2,2,2-pentafluoroethyl, R7 is haloa!kyl, preferably, trifluoromethyl, 2,2,2-trifīuoroethyl, or l,l,2,2,2-pentafluoroethyl, andR8 arehydrogen.(E) Yet another preferred compound of Formula (I) is that Rs is haloalkyl3-ene difluoromethyl, trifluoromethyl, 23232fluoroethyl3 or 13132,232-pentafluoroethyl and R7 and R8 are hydrogen. 34 (F) Yet the preferred group of compounds of Formula (I) that v / berein R6 is halocyclo, trifluoroethyl, trifluoromethyl / 1,2,2,2-trifluoroethyl, 1,1,2, \ t 2,2-pentafluoroethyl, R7 is halo, preferably, trifluoromethyl, 2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, andR8 arehydrogen.

[0119] (G) Yet anotber prefensd group of compounds of Formula (T) is that wherein R6 is baīoaIkyI, preferably, difluoromethyl, trifluoroinethyl; 2,2,2-irifhioroethyl, or 1,1,2,2,2-pentafIuoroethyl, R7 is alkyl, preferably, mefhyl, ethyl, or propyl, and R8 are hydrogen.(G) Yet an aberration of the group of compounds of Formula (T) that R6 is baoalkyl, preferably difluoromethyl, trifluoroethyl; 2,2,2-irifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R 7 is alkyl, preferably mefhyl, ethyl, or propyl, and R 8 are hydrogen.

[0120] (H) Yei anotber preferred group of compounds of Formula (I) is that wherein R6 is haloaikyI) preferably, l,l,2,2,2-pentafiuoroethyl or l,l,2,2,3,3,3-hepiafluoropropyl, R7 andR8 are hydrogen.(H) Ye anotber preferred group of Formula (I) that R6 is haloalkyl), 1,1,1,2,2,2-pentafluoroethyl or 1,1,1,2,3,3, 3-Hiafluoropropyl, R7 and R8 are hydrogen.

[0121] With the preferred groups (B)-(H), more preferred groups of compcunds are those v/herein R1, R2, R3, Rs, R/ and Rs ars as denned for group (A) above.With the preferred groups (B) - (H), R 1, R 2, R 3, R 5, R 5 and R 5 ars as denned for group (A) above.

[0122] With the preferred groups (D)-(īī), more preferred groups of compcunds are those vV'herein R1, R2, R&quot;. R4, andRs are as denned for group (A) abcve.With the preferred groups (D) - (short), R1, R2, R &quot;. R4, andRs are as denned for group (A) abcve.

[0123] it sbould be noted that reference to the preferred embodiments set forth above includes ali combinations ofparticular and preferred groups unless stated othenvise.It sbould be noted that reference is to the above mentioned examples unless stated othenvise.

[0124] Represenrative compound of the compound of Formula (I) where R' is bydrogen, RS is trifluoromethyl and other groups are as denned in Table I below are:Representative of the compound of Formula (I) where R 'is by hydrogen, RS is trifluoromethyl and other groups are as defined in Table I below are:

i v 35i v 35

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&lt;N vo LV 13669&lt; N vo LV 13669

3S3S

39LV 13669 p4 1 a ra * Ps g Λ xa- § a fv f rCi -P* *V -3- 03 a 0L, &amp; 03 a ā* Ū a 5}· 'S, &amp; ω 3 Pj &amp; Ū Λ t 1 * i t •a a -f ^ £ S 0 % f i a a 1 &amp; r—1 &amp; 0 1 1· Λ a 4 ό ^ 4Ϊ a a •t1 s, 2 s 1 a •ςτ &amp; •c 1 a a xr i—1 g P3 ,Pi * ^r hH a w ω K tt a w w a &gt;7-· w w w W W a a W »—&lt; £ ϋ o )-H O T cS es 1 0 1 co 1“ o fl s i? o 3 B a « &lt;o 3 © 1 1 w Ir o Λ o £ s* ¢3 o fl £ 3 03 Ί 0 rP 1 $ } &lt;N t 03 I 1 p w &gt;1 ’T A 3 o 3 &amp; o 03 I1 o J &amp; δ 3 Ί o a B O .w 1 0 i 03 1 &lt;D 1 a p a o 1—i &amp; o &amp; 0 1 1 03 -3 03 1 a o 1-4 a o &amp; Ū ! a &amp; £ rH 1- o a I1 03 &amp; &lt;2 *a 03 03 ā ? &lt;s $ o fi a o (-1 a 0 &amp; o B 1 a o | o f 43 ft 1“ 03 ? t o v-&lt; 0 1 &quot;O J N tS 03 a o ā P co (D a B 03 a 0 cd 1 § En ’a &amp; a o w • fH l' 03 a o a cd t ί§ p co % '&lt;—1 ϋ a % T pi 1 ’S ϋ 03 1? &lt;13 £ί B o rfl o &amp;1 «s o rp &quot;S f 03 i—-&lt; Ρ~ν 1 ļj C! 03 I 43 &amp;1 03 43 1 03 03 I1 03 P4 w a 1—1 H4 M )-H a M H-i V-i HH J-M h-1 w M a KH HH w Jt1 VH &gt;-rl &gt;a ^r1 hM J—rH ai W a a Pi % P4 · o 'V4 Ph o o o a o Vh a O 13 &gt;&gt;. o P^i &amp; a o &gt;—1 o O Ph O P O. o o &gt;* o &amp; p4 o * t o Ps o % &amp; K O o &gt;3 o a o K o ϋ &gt;&gt; o % 1 CO t O N cd Pi 1—1 &gt;&gt; a o Ih a o o &amp; a 0 1-4 a 13 o % &amp; i-H &amp; l- l o &amp; % a 0 1-4 a o 13 &gt;3 o &amp; H &amp; r“~4 o o B a o κ &amp; 13 &amp; *&gt;* a o Ih a o 13 o r——l P-» a o a o 13 P-» C3 ot O u a o I—( o &gt;v o ϊ&gt;Ί a o 1—( a o 13 &gt;&gt; o StereociLem. at **£ ***Q F * * Ci * * CQ * •—J F * * ftf * * w e? * * * * co&quot; * V—^ F * * fc; ·* ji Cq&quot; 4 e? * * * F * to w /~N * * * * * 6? * * # Co&quot; * * to * # # * * * to * \_/ * * * Lq * # to F * * * * co&quot; Ht F * * * to e? ·* * to * * to 6? * * * Co * * Co * S—' 6? * * * to * * λ Co* * * # to * * to * * * to * # CO e? * ·*· * to * to e? * # * C*3 * #- Co&quot; i- &amp; ’ό &amp; vo 00 Ό o\ Ό O I&gt; (N Γ- co I&gt; Tt i&gt; wn r- vo 1&gt; p- CQ l&gt; σ\ r- o co t—f 00 03 C3Q ro oo ^J· oo 4039LV 13669 p4 1 to ra * Ps g Λ xa- § fv f rCi -P * * V -3- 03 a 0L, &amp; 03 a                    & ω 3 PJ &amp; Λ t 1 * i t a a-f ^ £ S 0% f i a a &amp; r-1 &amp; 0 1 1 · Λ a 4 ό ^ 4Ϊ a a t1 s, 2 s 1 a • òτ &amp; • c 1 a a xr i-1 g P3, Pi * ^ r hH a w ω A w w a &gt; 7 · w w w W a a W &lt; £) o) -H O T cS es 1 0 1 co 1 'o fl s i? o 3 B a &lt; o 3 © 1 1 w And o 3 s £ 3 03 Ί 0 rP $ 1 &lt; N t 03 I 1 pw &gt; 1 'TA 3 o 3 &amp;; o 03 I1 o J & δ 3 Ί o a B O .w 1 0 i 03 1 &lt; d 1 a p a o 1 - i &amp; o &amp; 0 1 1 03 -3 03 1 a o 1-4 a o &amp; U! the &amp; £ rH 1- o a I1 03 & &lt; 2 * a 03 03 â ?? &lt; s $ o fi ao (-1 a 0 & o 1 oo | of 43 ft 1 &quot; 03? s &lt; 0 1 &quot; OJN S 03 ao c co (D a B 03 a 0 cd 1 § I &#39; l &gt; 03 &nbsp; &lt; 1 &gt;% 1 &lt; «So rp &quot; s f 03 i - &lt; Ρ ~ ν 1 l C 03 I 43 & 1 03 43 1 03 03 I1 03 P4 wa 1-1 H4 M) -H a M Hi Vi HH JM h -1w M a KH HH w Jt1 VH &gt; a ^ r1 hM J-rH a i W a P% P4 · o 'V4 Phoooo Vh a O 13 &gt; &gt; ao &gt; —1 o oo op o o o &gt; * o &amp; p4 o * to ps o% & o o o o oo o o o o o &gt; &gt; o% 1 CO t ON cd Pi 1— 1 &gt; ao Ih aoo & 0 1-4 a 13 o% & i &amp; l &amp;% a 0 1-4 ao 13 &gt; 3 &amp; & amp &amp; r &gt; ~ 4 oo B ao κ & 13 &amp; * &gt; * ao Ih ao 13 or —— l P- aoao 13 P- »C3 ot O uao I— (o &gt; vo ϊ &gt; o ao 1— (ao 13 &gt; &gt; o StereociLem at ** £ *** QF * * Ci * * CQ * • —JF * * ftf * * we? * * * co &quot; * V— ^ F * * fc; * * it Cq &quot; 4 e? * * * F * to w / ~ N * * * * * 6? * * # Co &quot; * * to * # # * * * to * \ _ / * * * Lq * # to F * * * * co &quot; Ht F * * * to e? · * * To * * to 6? * * * Co * * Co * S— '6? * * * to * * λ Co * * * # to * * to * * * to * # CO e? * · * · * To * to e? * # * C * 3 * # - Co &quot; i- &amp; 'Ό & vo 00 Ό o I O I &gt; (Γ co & & t t t t n n n vo 1 vo 1 g g g g g g

[0125] Representative compotuid of die compoimd of Formu la (T) where R1, R7 and RB are liyclrogen and other gronps are as defined. in Table Π below are: 41LV 13669 !-R2 X2Representative compoteid of die compimd of Form (T) where R1, R7, and RB are liyclrogen and other gronps are as defined. in Table Π below are: 41LV 13669! -R2 X2

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IZIZ

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GENERAL SYNTHETIC SCHEMEGENERAL SYNTHETIC SCHEME

[0126] Compounds of this invention can be made by the methods depicted in the reaction schemes shovm below.[0126] Compounds of this invention can be made by the methods depicted in the reaction schemes shovm below.

[0127] The starting materiāls and reaģents nsed in preparing these compounds are either available from commercial snppliers such as Aldiich Chemical Co., (Milwaukee, Wis.), Bachem (Toirance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods knovra to those skilled . in the art foliowing procedures set forth in references such as Fieser and Fieser's Reaģents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chenustry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Cheroistiy, (Jolm Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transfoimations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by vvhich the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having refeired to this disclosure.[0127] The starting material and reagents are as described in Aldiich Chemical Co., (Milwaukee, Wis.), Bachem (Toirance, Calif.), Or Sigma (St. Louis, Mo.). ) or are prepared by methods knovra to those skilled. Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chenustry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Cheroistiy (Jolm Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transfections (VCH Publishers Inc., 1989). These are some of the methods that are used in this article.

[0128] The starting materiāls and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materiāls may be characterized using conventional means, including physical constants and spectral data.[0128] The starting material and the intermediates of the reaction may be isolated, and are not limited to filtration, distillation, crystallization, chromatography and the like. Such material may be characterized by conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about-78 °C to about 150 °C, more preferably from ' about 0 °C to about 125 °C and mostpreferably at about room (or ambient) temperature, e.g., about 20 °C.Undetermined to the temperature range from about -78 ° C to about 150 ° C, more or less from about 0 ° C to about 125 ° C and mostpreferably at about room ( or ambient) temperature, eg, about 20 ° C.

[0129] In the reactions described hereinafter it maybe necessary to protect reactive functional groups, for example hydroxy, amino, imino, fhio or carboxy groups, rvhere these are desired in the final product, to avoid their rmwanted participation in the reactions. Conventional protecting groups may be used in accordance with Standard practice, for examples see T.W. Greene and P. G. M, Wuts in &quot;Protective Groups in Organic Chemistrf&quot; Jolm Wiley and Sons, 1999.Amino-imino, carboxy groups, carboxyl groups, carboxylic acids, carboxylic acids, carboxylic acids, etc. Conventional protection groups may be used with standard practice, for examples see T.W. Greene and P.G., Wuts in &quot; Protective Groups in Organic Chemistrf &quot; Jolm Wiley and Sons, 1999.

[0130] Compounds of Formula (Γ) where R1, R2, R3, R4, R5, R6 and R8 are as defined in the Summary of the Invention and R7 is hydrogen can be prepared by proceeding as in the follovring Reaction Scheme 1 helow. 45 45LV 13669Compounds of Formula (Γ) where R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are as defined in the Invention and Reaction Scheme 1 helow. 45 45LV 13669

SchemelSchemel

[0131] Reaction of a ketone of formula 1 where R6 aud R8 are as defined iu the Summaiy of the Inventiou with au a-amino ester of formula 2 where R is a cafboxy protecting group, preferably au alkyl group, preferably melhyl, aud R5 is as defined in the Summary of the Invention under reductive amination reaction conditions provide a compound of fonnula 3. The reaction is canied oui in the presence of a suitable dehydrating aģent such as TiCLļ, magnesinm sulfate, isopropyl trifluoroacetate, in the presence of a base such as diisopropylethylarmnes . pyridine, and the like and in a suitable organic solvent such as methylene chloride to give an imine. Ihe imine is reduced with a suitable reducing aģent such as sodium borohydride, sodium cyanoborohydride, and the like in a suitable organic solvent such as methanol, ethanol, and the like.Reaction of a ketone of formula 1 where R6 is a group of amino acids of formula 2 where R is a cafboxy protecting group, preferably a alkyl group, preferably melyl, aud R5 3) The reaction is as follows: TiCl3, magnesium sulfate, isopropyl trifluoroacetate, in the presence of a base such as diisopropylethylarmnes. pyridine, to give an imine. Cyanoborohydride is one of the most suitable agents for reducing the amount of alcohol in the body.

[0132] Compounds of fonnula 1 such as 2)2,2-trifluoromethylacetophenone and 2,2,2,4’-tetrafluoroacetophenone are commercially available. Others can be prepaied by methods well known in the art. α-Amino esters of formula 2 can be prepared by methods v/ell knovm in the arte.g., PCT Applications PubHcationNos. WO 03075836, WO 00/55144, WO 01/19816, WO 02/20485, WO 03/029200, U.S. Provisional Application No, 60/422,337, U. S. PatentNo. 6,353,017B1, 6,492,662B1, 6,353,017 B1 and 6,525,036B1, 6,229,011B1, 6,610,700, the disclosuies of which are incoīporated herein by referencē in their entirety.2-2,2-Trifluoromethylacetophenone and 2,2,2,4'-tetrafluoroacetophenone are commercially available. Others can be done by methods well known in the art. α-Amino esters of formula 2, PCT Applications PubHcationNos. WO 03075836, WO 00/55144, WO 01/19816, WO 02/20485, WO 03/029200, U.S. Provisional Application No. 60 / 422,337, U.S. PatentNo. 6,353,017B1, 6,492,662B1, 6,353,017 B1 and 6,525,036B1, 6,229,011B1, 6,610,700, the disclosuies of which are in their entirety in their entirety.

[0133] Hydrolysis of the ester group in compound 3 provides a compound of fonnula 4. The hydiolysis conditions depend on the nature of the protecting group. For example, whenR is alkyl the hydrolysis is canied out under aqueous basie hydrolysis reaction conditions to give the coiresponding acid of formula 4. The reaction is typically canied out vvith cesimn carbonate, lithium hydroxide, and the like in an aqueous alcohol such as methanol, ethanol, and the like.The hydrolysis of the ester group in compound 3 provides a compound of the compound 4. The hydrolysis of the ester group. For example, when the hydrolysis is can be out of the water, such as methanol, ethanol, and the like.

[0134] Compound 4 is then reacted with an a-hydroxyketoamide of formula 5 to give a compound of Fonnula 6. The reaction is typically cairied out in the presence of a suitable 46 coupling aģent e.g., benzotriazole-l-yloxytnspyrrolidinophosphoniuin hexafluorophosphate (PyBOP®), 04renzotriazon~yldViN,NVN'rietramethylmronium hezailuorophosphate (HBTU), 0- (7-azabenzotriazol-l-yl)-iJlJ3}3-tetramethyl-uronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl)-3-ethylcarbodiiniidehydrochloride (EDC), or l,3-dicyclohexyl-carbodiimide (DCC), optionallyinthepresence of l-hydroxy-benzotriazole (HOBT), and abase . such as N,N-diisopropylethylamrne, txiethylaimne; iV-methylinorpho]me, and the like. The reaction is typically canied out at 20 to 30 °C, preferably at about 25 °C, and requires 2 to 24 h to complete. Suitable reaction solvents are inert orgānic solvents such as halogenated orgānic solvents (e.g., metliylene chloride, chlorofonn, and the.like), acetonitrile, NŅ-dimethylfonnairiide, ethereal solvents siich as tetrahydrofuran, dioxane, and the like, [0135] Altematively, the above coupling step can be canied out by first converting 4 into an active acid derivative such as succinimide ester and then reacting it with an a-hydroxyketoamide of formula 5. The reaction typically requires 2 to 3 h to complete. The conditions utilized in this reaction depend on the nature of the active acid derivative. For example, if it is an acid chloride derivative of 4, the reaction is canied out in the presence of a suitable base (e.g. triethylamine, diisopropylethylacnine, pyridine, and the like). Suitable reaction solvents are polar organic solvents such as acetonitrile. JV^-dixnethylfonnamide, dichloromethane, or any suitable mixtuxes thereof. Compounds of formula 5 can be prepared by methods well knovvn in the art e.g., they can be prepared by the procedures described in PCT apphcation publication No. WO 02/1S369, the disclosure of which is incorporated herein by reference in its entirety, [0136] Oxidation of the hydroxyl group in compound 6 v/ith a suitable oxidizing aģent such as ΟΧΟΝΕ® provides a compound of Formula (I).Compound 4 is then reacted with a hydroxycetoamide of formula 5 to give a compound of Fillula 6. The reaction is typically cairied with a coupling agent, benzotriazole-1-yloxytnpyrrolidinophosphoniuin hexafluorophosphate (PyBOP®). ), 4-enzotriazonyl-N, N, N'-triramethylmronium hezailuorophosphate (HBTU), O- (7-Azabenzotriazol-1-yl) -I] - (3'-tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodine dihydrochloride ( EDC), or 1,3-dicyclohexyl-carbodiimide (DCC), optionalinthe-hydroxy-benzotriazole (HOBT), and abase. such as N, N-diisopropylethylamrne, txiethylaimne; iV-methylinorpho] me, and the like. The reaction is typically canied at 20 to 30 ° C, preferably at about 25 ° C, and requires 2 to 24 h to complete. Such as halogenated solvents (eg, methylene chloride, chlorofonn, and the.like), acetonitrile, NN-dimethylphenonide, ethereal solvents such as tetrahydrofuran, dioxane, and the like, [0135] The reaction typically requires 2 to 3 h to complete. The conditions utilized in this reaction depend on the active acid derivative. For example, if it is an acid chloride derivative of 4, the reaction is can be found in a suitable base (e.g., triethylamine, diisopropylethylacnine, pyridine, and the like). Suitable reaction solvents are polar organic solvents such as acetonitrile. N, N -dimethylphenamide, dichloromethane, or any suitable mixtuxes. Compounds of formula 5 in the PCT apphcation publication no. [0013] Oxidation of the hydroxyl group in compound 6 v / ith a suitable oxidizing agent such as provides® provides a compound of Formula (I).

[0137] Alteraatively, compounds of Formula (I) \vhere R1, R2, R3, R4, R5, R6 and Rs are as defined in the Summary of the Invention and R7 is hydrogen can be prepared by proceeding as in · the follorvine-Reaction Scheme 2 below.Alteratively, the compounds of Formula (I) vhere R1, R2, R3, R4, R5, R6 and R5 are hydrogen as defined by the inoculation procedure. Reaction Scheme 2 below.

Scheme 2Scheme 2

7 8 97 8 9

11 4 (I) 10 47LV 1366911 4 (I) 10 47LV 13669

Reaction of a compound of formula 8 where R5 is as defined irt the Summary of the Invention and PG is a suitable oxygen protecting group with a hemiacetal of formula 7 vvhere R6 is as defined im the Summary of the Invention provides an imiite compound of of formula 9. Treatment of 9 with an organolithium compound of formula R8Li where R8 is not hydrogen provides compound 10. Removal of the oxygen protecting group, followed by oxidation of the resulting alcohol 11 provides a compound of formula 4 vvliich is then oonverted to a compound of Formula (Γ) as described in Scherne 1 above. Suitable oxygen protecting groups and reaction conditions for putting them on and removing them can be found in Greene, T.W.: and Wuts, P. G. M.; Protecting Groups in Organic Synthesis\ John Wiley &amp; Sons, Inc. 1999.R5 is as defined in the Summary of the Invention. 10. Removal of the oxygen-protecting group 10. Removal of the oxygen protecting group 10. Removal of the oxygen protecting group 10. Formula (Γ) as described in Scherne 1 above. Suitable oxygen protecting groups and reaction conditions are described in Greene, T.W. and Wuts, P.G. M .; Protecting Groups in Organic Synthesis Sons, Inc. 1999

Altematively, compounds of Formula (ļ) where R1, R2, R3, R4, R5, R5 and R8 are as defined in the Sumraaiy of the Invention and R7 is hydrogen can be prepared by proceeding as in the follovving Reaction Scheme 3 below.Altematively, compounds of Formula (I) where R 1, R 2, R 3, R 4, R 5, R 5 and R 8 are as defined in the Reaction Scheme 3 below.

Scheme 3Scheme 3

(I) [0138] Reaction of an amino acid compound of formula 2 rvhere R is alkyl and R3 is as defined in the Summary of the Invention with a hemiacetal compound of formula 7 provides a 2-(l-hydroxy-2,2J2-trifluoroethylamino)acetate compound of formula 12. The reaction is canied out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid and in an aromatic hydrocarbon solvent such as toluene, beirzene, and the lihe.(I) Reaction of an amino acid compound of formula 2 is a 2- (1-hydroxy-2,2J2-) compound. trifluoroethylamino) acetate compound of formula 12. The reaction is can be found in the present invention.

[0139] Treatment of 12 with a compound of formula RSH where R8 is aiyl or heteroaryl under Friedel-Crafts reaction conditions or trialkylaluminum in toluene provides a compound of formula 3 v/hich is then converted to a compound of Formula (Γ) as described above. 48 [0140] Altematīvely, compounds of Formula (Γ) where R1, R2, R3, R4, R5, R6 and R8 are as defraed in the Smnmary of the iavention and R7 is hydrogen can be prepared by proceeding as in the following Reaction Scheme 4 below.Treatment of 12 with a compound of formula RSH where R8 is or heteroaryl under Friedel-Crafts reaction conditions or trialkylaluminum in toluene provides a compound of formula (Γ) as described above. [0140] Altemative compounds of Formula (Γ) where R1, R2, R3, R4, R5, R6 and R8 are as defined in the following Reaction Scheme 4 below.

Scheme 4Scheme 4

[0141] Reaction of a compound of formula 13 where R6 and R8 is as defined in Smnmary of the Invention with a compound of formula 14 where R’ is hydrogen or a carboxy protecting group and Rz is R5 or a precursor group (e.g., -allcylene-S-tīityl3 -a^lens-S-alķjdene-heteroaij'], and the like) to R5 group provides a compound of formula 15, The reaction is canied out in a suitable. organic solvent, including but not limited to, diethyl etber, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, and the like, or mixtures thereof and optionally in the presence of an organic or inorganic base. Preferably, the organic base iš triethylarmne, pyridine, N-methy3moxpholine, cohidine, diisopropyletliylamine, and the like. Preferahly, the inorganic base is cesi.um cafbonate, sodium carbonate, sodium bicarbonate, and the like. The reaction is optionally carried out in the presence of a drying aģent such as molecular sieves. Preferably, the reaction is carried out at room temperature. 49 49 LV 13669 [0142] Compounds of formula 13 can be prepared by methods well known in the art. For example, a compound of formula 13 where R8 is plienyl or 4-fluorophenyl and R6 is trifluoromethyl can be readily prepared from commercially available 2,2,2-trifluoroacetophenone or 2,2,2,41 -tetrafluoro acetophenone respectively, by reducing the keto group to an alcoholic group by suitable reducing aģent such as sodium borohydride, lithium alnminum hydride, and the like. The solvent used depends on the type of reducing aģent. For example, when sodium borohydride is used the reaction is carried out in an alcoholic organic solvent such as methanol, ethanol, and the like. When lithium aluminum hydride is used the reaction is canied out in an ethereal solvent such as tetrahydio&amp;ran, and the like. Reaction of 2,2,2-trifluoro-l-phenylethanol or 2,2,2-trifluoro-l-(4-fluorophenyl)ethanol with triflic anhydride or trifluoromethanesulfonyl chloride provides the desiied compound. Compounds of formula 13 where R7 and R8 are hydrogen and R6 is l,l,2,2,2-pentafluoroethyl can be prepared from conuuercially available 2,2,3,3,3-pentafluoropropan-l-ol can as desciibed above.Where R 'is hydrogen or a carboxy protecting group and Rz is R5 or a precursor group (eg, allcylene-S-tīityl3 -a ^ lens-S-aljdene-heteroai '], and the like) to R5 group provides a compound of formula 15, The reaction is canied out in a suitable. ethanol, toluene, xylene, ethanol, benzene, toluene, xylene, and the like. Preferably, the organic base of triethylarmne, pyridine, N-methy3moxpholine, cohidine, diisopropyletliylamine, and the like. Preferahly, the inorganic base is cesi.um cafbonate, sodium carbonate, and the like. The reaction is as a molecular sieve. Preferably, the reaction is carried out at room temperature. 49 49 EN 13669 Compounds of formula 13 well known in the art. For example, a compound of formula 13 where R8 is also phenyl or 4-fluorophenyl and R6 is trifluoromethyl can be readily prepared from commercially available 2,2,2-trifluoroacetophenone or 2,2,2,41-tetrafluoroacetophenone respectively, by reducing the lithium alnminum hydride, and the like. The solvent used depends on the type of reducing agent. For example, when the reaction is carried out in an alcoholic, ethanol, and the like. When the lithium hydride is used as a reaction, it can be used as a solvent and as such, and the like. Reaction of 2,2,2-trifluoro-1-phenylethanol or 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol with triflic anhydride or trifluoromethanesulfonyl chloride provides the desiied compound. Compounds of formula 13 where R7 and R8 are hydrogen and R6 is 1,1,2,2,2-pentafluoroethyl can be prepared from commercially available 2,2,3,3,3-pentafluoropropan-1-ol can as desciibed above.

Optically enriched compound of formula 15 can be obtained by reduction of the coiresponding halogenated acetophenone with a suitable reducing aģent such as catecholborane orBH3-DMS complex in the presence of a suitable catalyst such as (S) or (i?)-methyl CBS oxazaborolidine catalyst or (S) or (R)-ct,u -diphenyl-2-p&gt;iirolidine-methanol in the presence ofBBN to provide chiral alcohol which is then converted to compound 13 as described above. Compounds of formula 14 aie either commercially available or they can be prepared by methods well knovrn in •the art.OrBH3-DMS complex in the presence of a suitable catalyst such as (S) or (i?) - methyl CBS oxazaborolidine catalyst or (S) or (R) -ct, u-diphenyl-2-p &lt; g &gt; Compounds of Formula 14 • The Art.

[0143] Removal of the carboxy piotecting group from a compouad of formula 15 where R’ is a protecting group provides a compound of formula 16. The conditions used to remove the carboxy protecting group depenb on the nature of the caxboxy protecting group. For example, if R1 is alkyl, it is removed nnder basie hydxolysis reaction conditions utilizing aqueous base such as aqueous lithium hydroxide, sodium hydroxide, and the like in an alcoholic solvent such as methanol, ethanol, and the like. Additionally, if the R1 group in compound 14 is a precursor group to R5, it can be converted to R5 prior or after the ester hydrolysis step. 50 [0144] Compound 15 (where R’ is hydrogen) or 16 is then converted to an activated acid derivative 17 (X is a leaving group) and v/hich upon reaction with an aminoacetonitrile compouiid of formula 5 provides a compound of Formula (Γ) when Rz is R5 or aprecursor compound to (Γ) vvhen Rz is a precursor group to RD. The activated acid derivative can be prepared and then reacted with compound 5 in a stepwise manner or the activated acid derivative can be generated in situ in thepresence of compound 5. For evample, if the activated acid is acid halide it is first prepared by reacting 16 vrith a halogenating aģent such as ihionyl chloride, oxalyl chloride and the like and then reacted rvith compound 5. Altematively, the activated acid derivative is generated in situ by reacting compound 16 and 5 in the presence of a suitable coupling aģent e.g., henzotriazole-l-yloxytrispyrrolidinophosphoniumhexafluorophosphate (PyBOP®), 0-henzoiriazol-l-yl-7\fA[7V’VV'J-tetramethyl'Uronium hexaftuorophosphate (HBTU), 0- (7-azabenzotriazolri-yl)ri,l,3,3rietrame1hylmromumhexafluorophosphate (HATU), 1- (3-dimethylaininopropyl)-3-ethylcarhodiiinide hvdrochloride (EDC), l,3-dicyclohexyl-carbodiimide (DCC), an the like, optionally in the presence of l-hydroxybenzotiiazole (HOBT), and in the presence of a base such as iV^-diisopropylethylamine, triethvlamine, N-meihylmoipholine, and the like. Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chlorofoim, and the like), acetonitrile, A,A-dimethylformamide, ethereal solvents such aš tetrahydrofaran, dioxane, and the like. If R‘ is aprecursor group to R5, it is converted to R5 group to provide a compound of Formula (I) e.g, conversion of-alkylene-S-alkylene-heteroaryl to -alkylene-S02-alkyIene-heteroaryl under. oxidation reaction conditions.[0143] Removal of the carboxy piotecting group from a compose of formula 15 where R 'is a protecting group of formula 16. For example, if R1 is alkyl, it is removed by means of an aqueous lithium hydroxide, sodium hydroxide, and the like. Additionally, if the group is compound 14 is a precursor group to R5, it can be converted to R5 prior or after the ester hydrolysis step. Compound 15 (where R 'is hydrogen) or 16 is then a derivative of formula 5 provides a compound of Formula ( Γ) when Rz is R5 or aprecursor compound to (Γ) vvhen Rz is a precursor group to RD. The substance may not be present at the same time as the substance is present in the body. vrith a halogenating agent such as iodine chloride, oxalyl chloride and reacted rvith compound 5. Altematively, the activated acid derivative is in situ by reacting compound 16 and 5 -yloxytrispyrrolidinophosphoniumhexafluorophosphate (PyBOP®), 0-Henzo-thiazol-1-yl-7α [7V'VV'J-tetramethyl-Uronium hexaftuorophosphate (HBTU), 0- (7-azabenzotriazolyl) ri, 1,3,3-triramrame-1-methyl-hexafluorophosphate ( HATU), 1- (3-Dimethylaininopropyl) -3-ethylcarbodiol hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC), like in the presence of 1-hydroxybenzothiazole (HOBT), and in the presence of a base such as N-diisopropylethylamine, triethvlamine, N-meihylmoipholine, and the like. Such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, A, A-dimethylformamide, ethereal solvents such as tetrahydrofaran, dioxane, and the like. If R 'is a group R5, it is possible to convert from alkylene-S-alkylene-heteroarylalkylene-SO2-alkene-heteroaryl under. oxidation reaction conditions.

[0145] A compound of Formula (I) can be converted to other compounds of Formula (Γ). For exanaple: [0146] A compound of Formula (I) containing a hydroxy group may be prepared by de-alkylation/benzylation of an alkoxy/benzyloxy substituent; those containing an acid group, by hydrolysis of an ester group; and those containing a cyano, by displacement of a bromine atom on the corresponding compounds of Formula (I), A compound of Formula (I) containing a cyano group can be converted to a corresponding carboxy containing compound by hydrolysis of the cyano group. The carboxy group, in tum, can be converted to an ester group.[0145] A compound of Formula (I). For exanaple: A compound of Formula (I) containing a hydroxy group may be prepared by alkylation / benzylation of an alkoxy / benzyloxy substituent; those containing an acid group, by hydrolysis of an ester group; and containing a cyano, a compound of Formula (I) containing a cyano group containing a hydrolysis of the cyano group. The carboxy group, in tum, can be converted to an ester group.

[0147] A compound of Formula (I) can be prepared as a phaimaceutically acceptable acid addition salt by reacting the free base fonn of the compound with a pbarmaceutically acceptable 51 51LV 13669 . inorganic οι organic acid. Altematively, apharmaceutically acceptable base addition salt of a compound of Formula (ļ) can be prepared by reacting tlie free acid fonu of the compound v/ith a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula (I) are set fordi in the definitions section of this Application. Altematively, the salt foims of the compounds of Formula (Γ) can be prepared using salts of the starting materiāls or intermediates.A compound of Formula (I) can be used as a base for a compound of the invention. inorganic οι organic acid. Altematively, apharm-like base of a compound of the formula (s) can be prepared by reacting to a compound v. Inorganic and organic acids and bases are suitable for use in the preparation of compounds of formula (I). Altematively, the salt foims of the formula (Γ) can be prepared using the orthogonal material or intermediates.

[0148] The free acid or free base fonns of the compounds of Formula (Γ) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula (I) in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., aīnmonium hydroxide solution, sodium hydroxide, and ihe like). A compound of Formula (Γ) in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).[0148] The free acid or free base of the formula (Γ) For example, a compound of Formula (I) is an acid addition salt form (e.g., amonmonium hydroxide solution, sodium hydroxide, and ihe like). A compound of Formula (Γ) in a base addition salt form is suitable for treating with a suitable acid (e.g., hydrochloric acid, etc).

[0149] The N-oxides of compounds of Formula (I) can be prepared by methods knorvn to those of ordinary skill in the art. For eXample, jV-oxides can be prepared by treating an unoxidi2ed form of the compound of Formula (I) with an oxidizing aģent (e.g., trifluoroperacetic acid, pemialeic acid, perbenzoic acid, peraceiic acid, ?«e/a-chloroperoxybenzoic add, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromefliane) at approximate!y 0°C. Altemaiively, the A'-oxides of the compounds of Formula (I) can be prepared from- the N-oxide of an appropriate starting material.[0149] The N-oxides of compounds of Formula (I) EXample, n-oxides can be prepared by treating an unoxidized form of the compound of Formula (I) with an oxidizing agent (eg, trifluoroperacetic acid, piacleic acid, perbenzoic acid, peraceiic acid,? / A-chloroperoxybenzoic add, or the like) in a suitable inert organic solvent (eg, halogenated hydrocarbon such as dichloromefliane) at approximate! 0 ° C. Altemaiively, the A-oxides of the Formula (I) can be prepared from- the N-oxide of an appropriate starting material.

[0150] Compounds of Formula (Γ) in unoxidized form can be prepared fromiV-oxides of compounds of Formula (I) by treating with a reducing aģent (e.g., sulfirr, sulfur dioxide, txiphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus tricMoride, tribromide, or the like) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C. ]0151] Prodrag derivatives of the compounds of Formula (I) can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Sanlnier et al.(1994), Bioorganic and Medicīnai Chemislry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized componnd of Formula 0) with a suitable carbamylating aģent (e.g., l,l-acyloxyalkylcarbonochloridate,pūrn-nitrophenyl carbonate, or the like).Compounds of Formula (Γ) in unoxidized form can be prepared by a reducing agent (eg, sulfirr, sulfur dioxide, txiphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus tricMoride) , tribromide, or the like) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 ° C. ] 0151] Prodrag of the compounds of Formula (I), for further details see Sanlnier et al. (1994), Bioorganic and Medical Chemislry Letters, Vol. 4, 1985). For example, with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloride, n-nitrophenyl carbonate, or the like).

[0152] Protected derivatives of the compounds of Formula (Γ) can be made by means knovvn to those of ordinaxy skill in the art. A detailed description of the techniqu.es applicable to the 52 creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synihesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999.[0152] Protected derivatives of the compounds of Formula (Γ) can be made by means of the art of skill in the art. The detailed description of the technics.es applicable to the creation of a group of children and their removal can be found in T.W. Greene, Protecting Groups in Organic Synihesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999

[0153] Compounds of tlie present invention may be convemently prepared or fonned duiing the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of thepresent invention may be convemently prepared byrecrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydxoftiran or metlianol.[0153] Compounds of the present invention may be in the form of convents or in the process of the invention, as solvates (e.g., hydrates). Hydrates of thepresent invention may be made by means of organic solvents such as dioxin, tetrahydxoftyran or methylanol.

[0154] Compounds of Formula (I) can be prepared as their individual steieoisomers by reacting a racemic mixture of the compound with an optically active resolving aģent to fonn a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. &quot;Ϋ/ΜΙε resolution of enantiomers canbe canied out using covalent diasteromeric derivatives of compounds of Formula (I), dissociable complexes areprefeired (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferablv, by separation/resolution tecbniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving aģent, by any practical ' means that would not result in racemization. A more detailed.description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resoīutions, John Wiley.&amp; Sons, Inc, (1981).Compounds of Formula (I) can be used in the preparation of the compounds of the invention. &quot; Ϋ / ΜΙε resolution of enantiomers canbe out using covalent diasteromeric derivatives of Formula (I), dissociable complexes areprefeired (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.). The diastereomers can be separated by solving in solubility. The optically pure enantiomer is then recovered, along with the resolving agent. A more detailed.description of the stereochemistry of a racemic mixture can be found in Jean Jacques Andre Collet, Enantiomers, Racemates and Resoils, John Wiley. &Amp; Sons, Inc., (1981).

Preparation of Biological Aģents [0155] In practicing this invention several processes for the generation or purification of biological aģents are us^d. Methods for preparing the biologics are well Ιαιον/η in the art as discussed below.Preparation of Biological Agent [0155] Practices of Biological Agents are us ^ d. Methods for preparing the biology are well discussedαιον / η in the art as discussed below.

[0155] Monoclonal antibodies can be prepared using Standard techniques well knovm in fhe art such as by the method of Kobler and Mlstein, Nature 1975,256:495, or a modīfication thereof, such as described by Buck et al. 1982, In Vitro 18:377. Typically, a mouse or rat is immunized with the MenB PS derivative conjugated to aprotein carrier, boosted and the spleen (and optionally several large lymph nodēs) reinoved and dissociated into single celis. īf desired, the spleen celis may be screened (after removal of non-speciiīcally adherent celis) by applying a celi suspension to a plate or well coated with the antigen. B-cells, expressing membrane-bound immunoglobulin specific for the antigen, wīll bind to the plate, and will not be rinsed away vvith 53 53 LV 13669 the rest of the suspension. Resulting B-cells, or ali dissociated spleen celis, are then induced to iiise witli myeloma celis to fonn hybridomas. Representative muiiae myeloraa lines for use in the hybridizations include those available from the American Type Cultare Collection (ATCC).Monoclonal antibodies can be prepared using standard techniques such as the method of Kobler and Mlstein, Nature 1975, 256: 495, or as described by Buck et al. 1982, In Vitro 18: 377. Typically, a mouse or rat is immunized with the MenB. the spleen cell may be screened (after removal of the non-specylic adherent cell) by applying a cell suspension. B-cells, expressing membrane-bound immunoglobulin specific for the antigen, binding to the plate, 53 53 EN 13669 the rest of the suspension. Resulting B-cells, or ali-dissociated spleen cells, are then induced to a hybrid myeloma pathway to fon hybridomas. Representative muiiae myelora lines for use in the hybridizations include those available from the American Type Cultare Collection (ATCC).

[0157] Chimeric antibodies composed ofhuman and non-human amino acid sequences may be fonned from the mouse monoclonal antibody molecules to reduce their immunogenicity ia humāns (Winter et al. Nature 1991 349:293; Lobuglio et al. Proc. Nat. Ācaā. Sci. USA 1989 86:4220; Shaw et al. J. Immunol. 1987 138:4534; and Brown et al. CaneerP.es. 1987 47:3577; Riechmann et al. Nature 1988 332:323; Verhoeyen et al. Science 1988 239:1534; and Jones et al. Nature 1986 321:522; EP Publication No.519, 596, published Dec. 23, 1992; and UX Patent PublicationNo. GB 2,276,169, published Sep. 21,1994). . [0158] Antibody molecule fragments, e.g., F(ab')2, FV, and sFv molecules, that aie capable of exhibiting iromunological binding properties of the paient monoclonal antibody molecule can be produced nsing knomi techniques. Inbar et al Proc. Nat. Acad. Sci. USA 1972 69:2659; ' Hochman et al. Biochem. 1976 15:2706; Ehrlich et al. Biochem. 1980 19:4091; Huston et al. Proc. Nat. Acad. Sci. USA 1988 85(16):5879; and U.S. Pat. Nos. 5,091,513 and 5,132,405, and U.S. Pat. No. 4,946,778.[0157] Chimeric antibodies of the human and non-human amino acid sequences may be derived from the mouse (Winter et al. Nature 1991 349: 293; Lobuglio et al. Proc. Nat. Sci. USA 1989 86: 4220, Shaw et al J. Immunol 1987 138: 4534, and Brown et al., CaneerP.es 1987 47: 3577; Riechmann et al. Nature 1988 332: 323; Verhoeyen et al. Science 1988 239: 1534; and Jones et al. Nature 1986 321: 522; EP Publication No. 519, 596, published Dec. 23, 1992; and UX Patent Publication No. GB 2,276,169, published Sep. 21, 1994). . Antibody molecule fragments, e.g., F (ab ') 2, FV, and sFv molecules, that are capable of exhibiting irrelevant properties. Inbar et al. Proc. Nat. Acad. Sci. USA 1972 69: 2659; 'Hochman et al. Biochem. 1976, 15: 2706; Ehrlich et al. Biochem. 1980 19: 4091; Huston et al. Proc. Nat. Acad. Sci. USA 1988 85 (16): 5879; and U.S. Pat. Well. 5,091,513 and 5,132,405, and U.S. Pat. No. 4,946,778.

[0159] In the altemative, a pliage-display system can be used to expand the monoclonal antibody molecule populations in vitro. Saiii, et al. Nature 1986 324:163; Scharf et al. Science 1986 233:1076; U.S. Pat. Nos. 4,683,195 and 4,683,202; Yang et al. J. Mol. Biol. 1995 254:392; Barbas, ΙΠ et al. Methods: Comp. Meth Enzymol. 1995 8:94; Barbas, ΙΠ et al. Proc. Nati. Acad. Sci. USA 1991 88:7978.[0159] In vitro-display system can be used in vitro. Saiii, et al. Nature 1986 324: 163; Scharf et al. Science 1986 233: 1076; U.S. Pat. Well. 4,683,195 and 4,683,202; Yang et al. J. Mol. Biol. 1995 254: 392; Barbas, et al. Methods: Comp. Meth Enzymol. 1995 8:94; Barbas, et al. Proc. Nati. Acad. Sci. USA 1991 88: 7978.

[0160] The coding sequences for the heavy and light chain portions of the Fab molecules selected from the phage display library can be isolated or synthesized, and cloned into any suitable vector or replicon for expression. Any suitable expression system can be used, including, for example, bacterial, yeast, insect, amphibian and mammalian systems. Expression systems in bacteria include those described in Chang et al. Nature 1978 275:615, Goeddel et al. Nature 1979 281:544, Goeddel et al. NucleicAcids Res. 1980 8:4057, European Application No. EP 36,776, U.S. Pat. No. 4,551,433, deBoer et al. Proc. Nati. Acad. Sci. USA 1983 80:21-25, and Siebenlist et al. Celi 1980 20:269. '[0161] Expression systems in yeast include those described in Hinnen et al. Proc. Nati. Acad. Sci. USA 1978 75:1929, Ito et al. J Bacterial 1983 153:163, Kurtz et al. Mol. Celi. Biol. 1986 6:142, Kunze et al. J. Basic Microbiol. 1985 25:141, Gleeson et al. J. Gen. Microbiol 1986 54 132:3459, Roggenkamp et al. Mol. Gen. Genet. 1986 202:302, Das et al. J. Bacteriol. 1984 158:1165, De Louvencourt et al. J. Bacteriol. 1983 154:737, Van den Berg et al. Bio/Technology 1990 8:135, Kunze et al. J. Basic Microbiol. 1985 25:141, Cregg et al. Mol. Celī. Biol. 1985 5:3376, U.S. Pat. Nos. 4,837,148 and 4,929,555, Beach et al. Nature 1981 300:706, Davidow et al. Curr. Genet. 1985 10:380, Gaillardin et al. Curr. Genet. 1985 10:49, Ballance et al. Biochem. Biophys. Res. Commun. 1983 112:284-289, TiTbum et al. Gene 1983 26:205-221, Yelton et al. Proc. Nati Ācad. Sci. USA 1984 81:1470-1474, ICel]y et al EMBOJ. 19.85.4:475479; European Application No. BP 244,234, and Intemational Publication No. WO 91/00357.[0160] The coding sequences for the heavy and light chain portions of the Fab molecules selected from the phage display library can be isolated or synthesized. Any suitable expression system, including, for example, bacterial, yeast, insect, amphibian and mammalian systems. Expression systems in bacteria include those described in Chang et al. Nature 1978 275: 615, Goeddel et al. Nature 1979 281: 544, Goeddel et al. NucleicAcids Res. 1980 8: 4057, European Application No. EP 36,776, U.S. Pat. Pat. No. 4,551,433 to de Boo et al. Proc. Nati. Acad. Sci. USA 1983 80: 21-25, and Siebenlist et al. Cell 1980 20: 269. 'Expression systems in yeast include those described in Hinnen et al. Proc. Nati. Acad. Sci. USA 1978 75: 1929, Ito et al. J Bacterial 1983 153: 163, Kurtz et al. Mol. Great. Biol. 1986 6: 142, Kunze et al. J. Basic Microbiol. 1985 25: 141, Gleeson et al. J. Gen. Microbiol 1986 54 132: 3459, Roggenkamp et al. Mol. Gen. Genet. 1986 202: 302, Das et al. J. Bacteriol. 1984, 158: 1165, De Louvencourt et al. J. Bacteriol. 1983, 154: 737, Van den Berg et al. Bio / Technology 1990 8: 135, Kunze et al. J. Basic Microbiol. 1985 25: 141, Cregg et al. Mol. Celi. Biol. 1985 5: 3376, U.S. Pat. Pat. Well. 4,837,148 and 4,929,555, Beach et al. Nature 1981 300: 706, Davidow et al. Curr. Genet. 1985 10: 380, Gaillard et al. Curr. Genet. 1985 10:49, Ballance et al. Biochem. Biophys. Res. Commun. 1983, 112: 284-289, TiTbum et al. Gene 1983 26: 205-221, Yelton et al. Proc. Nati Ācad. Sci. USA 1984 81: 1470-1474, ICel] y et al EMBOJ. 19.85.4: 475479; European Application No. BP 244,234, and Intemational Publication No. WO 91/00357.

[0162] Expiession of heterologous genes in iasects can be accomplished as described inU.S. Pat. No.· 4,745,051, European Application Nos. EP 127,839 and EP 155,476, Vlak et al. J. Gen. Virol. 1988 69:765-776, Miller et al. Ann. Rev. Microbiol. 1988 42:177, Carbonell et al. Gene 1988 73:409, Maeda etaī. Nature 1985 315:592-594, Lebacq-Verheyden et al.Mol. Celi. Biol. 1988 8:3129, Smiih et al. Proc. Nati. Ācad. Sci. USA 1985 82:8404, Miyajima et al Gene 1987 58:273, and Martin ei al. DNA 1988 7:99. Numerous baculoviral sirains and variants and corresponoing permissive insect hosi celis from tosts are described in Luclcow et al.Expiession of heterologous genes in iasects can be accomplished as described inU.S. Pat. No. · 4,745,051, European Application Well. EP 127,839 and EP 155,476, Vlak et al. J. Gen. Virol. 1988 69: 765-776, Miller et al. Ann. Rev. Microbiol. 1988 42: 177, Carbonell et al. Gene 1988 73: 409, Maeda et al. Nature 1985 315: 592-594, Lebacq-Verheyden et al. Great. Biol. 1988 8: 3129, Smiih et al. Proc. Nati. Acad. Sci. USA 1985 82: 8404, Miyajima et al Gene 1987 58: 273, and Martin no. DNA 1988 7:99. Numerous baculoviral sirains and variant and corresponoing permissive insect hosi cels from tosts are described in Luclcow et al.

Bio/Technology 1988 6:47-55, Miller et al. GENETICENG1NEER1NG, Setlow, J. K. etal. eds., Vol. 8, Plenum Publishing, pp. 1986 277-279, and Maeda et al Nature 1985 315:592-594.Bio / Technology 1988 6: 47-55, Miller et al. GENETICENG1NEER1NG, Setlow, J. K. et al. eds., Vol. 8, Plenum Publishing, p. 1986 277-279, and Maeda et al Nature 1985 315: 592-594.

[0163] Mammalian expression can be accomplished as described in Dijkema et al. EMBO J. 1985 4:761, Gonnan et al Proc. Nati Ācad. Sci. USA 1982 79:6777, Boshart et al. Celi 1985 41:52l, and U.S. Pat. No. 4,399,216. Other features of mammalian expression can be facilitated as described in Hana et al Meth. Enz. 1979 58:44, Barnes et al. Ānal. Biochem. 1980 102:255, U.S. Pat Nos. 4,767,704,4,657,866, 4,921,162, 4,560,655 and Reissued U.S. Pat. No. RE 30,985, and in Intemational Publication Nos. WO 90/103430, WO 87/00195.[0163] Mammalian expression can be accomplished as described in Dijkema et al. EMBO J. 1985 4: 761, Gonna et al. Proc. Nati Ācad. Sci. USA 1982 79: 6777, Boshart et al. Cell 1985 41: 52l, and U.S. Pat. No. 4,399,216. Other features of mammalian expression can be facilitated as described in Hana et al Meth. Enz. 1979, 58:44, Barnes et al. Outside. Biochem. 1980 102: 255, U.S. Even Well. 4,767,704,4,657,866, 4,921,162, 4,560,655 and Reissued U.S. Pat. No. RE 30,985, and in Intemational Publication Well. WO 90/103430, WO 87/00195.

[0164] Theproduction of recombinant adenoviral vectors are described in U.S. Pat. No. 6,485,958.[0164] The production of recombinant adenoviral vectors are described in U.S. Pat. No. 6,485,958.

[0165] Botulinum toxin type A can be obtained by establishing and growing cultures of Closiridium botulinum in a fennenter and tlien harvesting andpurifying tbe feimented mbcture in accordance with knovrn procedures.[0165] Botulinum toxin type A and a cultivation of Closiridium botulinum in a herb and harvesting and purifying tbe feimented mbcture initing with knovrn procedures.

[0166] Any of the above-described protein production metliods can be used to provide the biologic that would benefit from the present invention. 55 55LV 13669[0166] Any of the above-described protein production metlods can be used to provide the biological. 55 55LV 13669

Pharmacologv and Utilitv [0167] The compounds of the invention are selective inhibitors of cysteine proteases such as cathepsin S, K, B, and/or F, and in particular cathepsin S, and accordingly are useful for treating diseases in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease, For example, the compounds of the invention are useful in treating autoimmune disorders, including, but not Limited to, juvenile onset diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Gravēs' disease, myastheraa grāvis, systemic lupus erythemotasus, rhemnatoid artbritis and Hashimoto's thyxoiditis, allergic disorders, including, but not Limited to, astbma, allogeneic iminune responses, including, but not Limited to, organ transplants or tissue grafis and endomehiosis.Pharmacologist and Utilitv [0167] The compounds of the invention are selective inhibitors of cysteine proteases such as cathepsin S, K, B, and, in particular, cathepsin S, and. juvenile onset diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Gravēs' disease, myasthera ditch, systemic lupus erythematosus, rhemnoidoid arthritis and Hashimoto's thyroidoid, allergic disorders, including but not limited to, organ transplants or tissue grafis and endomehiosis.

[0168] Cathepsin S is also implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneurnonities and cardiovascular disease such as plaque rupture and atheroma, Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsms S are of use in treatment of systemic amyloidosis.Cathepsin S is also implicated in disorders involving extensive elastolysis, such as chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, and cardiovascular disease such as plaque rupture and atheroma. implicated in fibril formation and, therefore, inhibitor of cathepsms.

[0169] The cysteine protease inhibitoiy activities of the compounds of Formula (I) can be deteimined by methods known to those of ordinary sldll in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by tēst compounds are known. Typically, the assay measures protease-induced hydrolysis of a peptide-based substrate. Details of assays for measuring protease inhibitoiy activity are set forih in Biological Examples 1-5, infra.The cysteine protease inhibition activities of the formula (I) can be deteimined by methods known in the art. Suitable in vitro assays for measuring protease activity and inhibition by compounds are known. Typically, the assay measures a peptide-based substrate. Details of assays for measuring protease inhibition activity are set forih in Biological Examples 1-5, infra.

Administration and Phamaceutical Compositions [0170] In general, compounds of Formula (I) will be administered in therapeuticallv effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic aģents. A 1herapeutically effective amount may vary •widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula (I) may range from about 10 micrograms per kilogram body weight (pg/kg) per day to about 100 milligram per kilogram body weight (mg/kg) per day, typically firom about 100 pg/kg/day to about 10mg/kg/day. Therefore, a therapeutically effective amount for an 80 kg human patient may range from about 1 mg/day to about 8 g/day, typically jfirom about 1 mg/day to about 800 mg/day. In general, one of ordinary skill in the art, 56 acting in reliance upon personai knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a componnd of Formula (I) fortreating a given disease.Administration and Phamaceutical Compositions [0170] In general, the compounds of Formula (I) will be administered in a therapeutic manner. The 1herapeutically effective amount may be varied according to the severity of the disease. About 100 micrograms per kilogram body weight (pg / kg) per day to about 100 milligrams per kilogram body weight (mg / kg) per day, typically firom about 100 pg / kg / day to about 10mg / kg / day. Therefore, the therapeutically effective amount for an 80 kg / day to about 8 g / day human patient may range from about 1 mg / day to about 800 mg / day. In general, one of the ordinary skill in the art, is a method of treating a disease.

[0171] The compounds of Formula (I) can be administered as phannaceutical compositions by one of the follorving rontes: oral, systemic (e.g., transdemial, intranasal or by suppository) or parenteral (e.g., iniramuscular, intravenous or subcutaneous). Compositions can take the fonn of tablets, pilis, capsules, semisolids, powders, sustained release fommlations, Solutions, suspensions, elbdrs, aerosols, or any other appropriate composition and are comprised of, in general, a componnd of Formula (I) in combination v/ith at least one phaxmaceutically acoeptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.Oral, systemic (e.g., transdemial, intranasal, or suppository) or parenteral (e.g., iniramuscular, intravenous or subcutaneous) compounds. Compositions can take the fonn of tablets, capsules, semisolids, powders, sustained release fommlations, solutions, suspensions, elbdrs, spray, or any other form of formula (I) in combination v / ith at least one phaxm v acoeptable excipient. Acceptable excipients are non-toxic. Such excipient may be in any solid, liquid, semisolid or, in the case of an aerosol composition, is an alternative to one of the skill in the art.

[0172] Solid phannaceutical excipients include starch, cellulose, talc, glucose, lactose, .sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selectēd from water, ethanol, gIycerol, propylene glycol and various oils, including those of petroleum. animal, vegetable.or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Prefened liquid carriers, particularly forinjectable Solutions, include water, saline, aqueous dextrose and glycols.Solid phannaceutical excipients include starch, cellulose, talc, glucose, lactose, .sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycol, propylene glycol and various oils including those of petroleum. animal, vegetable.or synthetic origin (eg, peanut oil, soybean oil, mineral oil, sesame oil, and the like). Prefened liquid carriers, especially forinjectable solutions, include water, saline, aqueous dextrose and glycols.

[0173] The amount of a compound of Fomrula (I) in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors knovm to those of skill in the art of phannaceutical Sciences. In general, a composition of a compound of Formula (I) for treating a given disease will comprise from 0.01%w to 90%w, preferably 5%w to 50%w, of active ingredient with the remainder being the excipient or excipients. Preferably the phannaceutical composition is administered in a single unit dosage forrn for continuous treatment or in a single unit dosage form ad libitum vvhen relief of symptoms is speci£cally reqnixed. Representative phaimaceutical formulations containing a compound of Formula (Γ) are described below. 57 57LV 13669The amount of a compound of Fomrula (I) in the composition may vary according to the nature of the unit dosage. In general, a composition of a compound of formula (I) for treating a disease will be from 0.01% w to 90% w, preferably 5% w to 50% w, of active ingredient with the remainder being the excipient or excipients. Preferably, a single unit dosage form may be used for the purpose of the present invention. Representative physiological formulations containing a compound of Formula (Γ) are described below. 57 57LV 13669

Examples [0174] The present invention is further exemplified, hut not limited by, the following examples that illustrate the preparation of compounds of Formula (I) (Examples) and intennediates (References) according to the invention.Examples [0174] The present invention is further exemplified by reference to the invention.

Reference AReference A

[0175] Synthesis of trifluoromethanesulfonic acid 2,2,2-trifluoro-l-(4-fluorophenyl)ethyl esterSynthesis of trifluoromethanesulfonic acid 2,2,2-trifluoro-1- (4-fluorophenyl) ethyl ester

Step 1Step 1

To a stiired solution of 2,2.2,4’-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBiL (0.98 g, 26.5 mmol) at 0° C. After stiiring at25° C for2 h, the reaction mixtuxe v^as quenched by adding 1N HC1 (100 mL) and then extracted with ethyl ethei. The ether extract was washed with brine, diied vrith MgSCh, and concentrated to give 2,2,2-iriiluoio-l-(4-fluorophenyl)ethanol (11.32 g) which was nsed in next step without iurther pmification. .To a solution of 2,2,2,4'-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBiL (0.98 g, 26.5 mmol) at 0 ° C. After drawing at 25 ° C for 2 h, reaction mixtuxe or quenched by adding 1N HCl (100 mL) and then extracted with ethyl ethe. The ether extract was washed with brine, and concentrated to give 2,2,2-irylthio-1- (4-fluorophenyl) ethanol (11.32 g) which was nsed in next step without further information. .

Step 2Step 2

NaH (640 mg, 16nunol, 60% in mineral oil) was washed twice withhexane (20 mL) and then suspended in dhied diethyl ether (20 mL). A solution of 2,2,2-trifhioro-l-(4-£luoro-phenyl)ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0° C. After stining for 2 h at room temperature, a solution of trifhioromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by adding a solution of NaHC03 and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to yield trifluoromethanesulfonic acid 2,2,2-trifluoro-l -(4-fluorophenyl)ethyl ester (3.3 g). 58NaH (640 mg, 16nol, 60% in mineral oil) was washed twice withhexane (20 mL) and then suspended in diethyl ether (20 mL). A solution of 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0 ° C. After stining for 2 h at room a solution of trifluoromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by a solution of NaHCO 3 and the product was extracted with diethyl ether. 2,2,2-Trifluoro-1- (4-fluorophenyl) ethyl ester (3.3 g). 58

Reference BReference B

Synthesis of2,2,2-trifluoro-l(R) -(4-fhiorophenyl)ethanol QF3Synthesis of 2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethanol QF3

[0176] To a -78 °C toluene (25 mL)/dichloroinethane (25 mL) solution of 2,2,2,4’-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M d'-meihjl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added fieshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at -7 8 °C for 16 h at -\vhich iime 4N HC1 (5 mL in dioxane) was added and the reaction mixture was allowed to wann to room temperature. The reaction mixtnre was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was . dried over magūesium sulfāts, filtered and concentrated to provide a solid. The solid was suspenaed in hexanes and filtered off. The hexanes filirate containing the desired product was concentrated and the residue subjected to fiash chromatography (10 hexanes: 1 ethylacetate) to provide the tītie compound as colorless oil (2.2g, 87% yield). Theratio of enantiomers was detennined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanolmobile phass. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.).To -78 [deg.] C. toluene (25 mL) / dichloroethane (25 mL) solution of 2,2,2,4'-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M dichloromethane CBS oxazaborolidine catalyst (1.3 g). mL, 1.3 mmol) was added fieshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at -7 8 ° C for 16 h at 4N HCl (5 mL in dioxane). The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was. dried over magesium sulfate, filtered and concentrated to provide a solid. The solid was suspenaed in hexanes and filtered off. The hexanes filirate containing the desired product as colorless oil (2.2g, 87% yield). Thermation of enantiomers was detected 95: 5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phass. Ret. Time major product 6.757 min. Ret. Time minor isomer 8.274 min.).

Reference DReference D

Synthesis of 2(R)-[2,2,2-trifluoro-1 (5)-(4-fluorophenyl) ethylarmno]-3-tritylsulfanylpropionic acidSynthesis of 2 (R) - [2,2,2-Trifluoro-1 (5) - (4-fluorophenyl) ethylarmno] -3-tritylsulfanylpropionic acid

[0177] To a slurry of S-trityl-L-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL/g AA) at room temperature was added diisopropylethylamine (9.32 mL, 53.48 mmol) followedby a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro-l (R5)-phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane (15 mL) via syringe ali at once. After 19 h, the reaction mbcture was concentrated on the rotovap to give an oil. Diethyl eiher was added and the solution was washed with IN HC1 and brine. The organic layer was 59 59LV 13669 dried over MgSO^ filtered, and concentrated. Flash clxromatography of the residue with 2 hexanes/l ethyl acetate/.25% acetic acid as the eluentprovided 2(i?)-[2&gt;2J2-trifluoro-l(AS)'(4-fluorophenyl)ethylainiiio]-3-tritylsuIfarLyl-propionic acid (6 g) (major diastereomer (R,S), 90 de) as an oil/foam.A slurry of S-trityl-L-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL / g AA) was added diisopropylethylamine (9.32 mL, 53.48 mmol) followedby a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro-1 (R5) -phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane (15 mL) via syringe ali at once. After 19 h, the reaction mbcture was concentrated on the rotovap to give an oil. Diethyl noher was HCl and brine. The organic layer was 59 59LV 13669 dried over MgSO 4 filtered, and concentrated. 2 x 2-trifluoro-1 (AS) '(4-fluorophenyl) ethynyl] -3-tritylIfarLyl -propionic acid (6 g) (major diastereomer (R, S), 90 de) as an oil / foam.

Reference EReference E

Synthesis of 2-(l -aminocyclopropyl)-lV'-cyclopropyI-2-hydroxyacetamideSynthesis of 2- (1-Aminocyclopropyl) -1V'-cyclopropy-2-hydroxyacetamide

Stepi [0178] 1-Arninocyclopropanecarbonitrile chloiohydrate (6.1 g3 51.4 mmol) was refluxed in 6N hydrochloiic acid (500 mL) for 7 h and then concentrated to yield l-aminocyclopropane- : carboxylic acid chlorohydrate as an o£f-white solid rvhich was used in the next step ^ithout further purification.Stepi 1-Arnocyclopropanecarbonitrile chloiohydrate (6.1 g3 51.4 mmol) was refluxed in 6N Hydrochloric Acid (500 mL) for 7 h and then concentrated to yield the title compound: carboxylic acid chlorohydrate. used in the next step ithout further purification.

Step 2 [0179] A solution of l-aminocyelopropanecarboxylic acid chlorohydrate (3.6 g, 26.2 mmol) in MeOH (100 mL), containing potassium carhonate (4.0 g3 28.94 mmol) was stiired at room temperature for 48 h. After filtration. MeOH v/as removed under reduced pressure to yield 1-aminocycIopropanecarboxylic acid (2.64 g) v/hich was usedin the next step without further purification.Step 2 A solution of 1-aminocyclopropanecarboxylic acid chlorohydrate (3.6 g, 26.2 mmol) in MeOH (100 mL) containing potassium carhonate (4.0 g 3 28.94 mmol) was stirred at room temperature for 48 h. After filtration. MeOH v / as removed under reduced pressure to yield 1-aminocyclopropanecarboxylic acid (2.64 g) v / hich was used in the next step without further purification.

Step 3 [0180] l-Aminocyclopropanecarboxylic acid (2.64 g, 26,1 mmol) and tetramethylammomum hydroxide (2.38 g, 26.1 mmol) was added to acetonitrile (150 mL). The reaction mixtuxe became homogeneous after stining at room temperature for about an honr. B0C2O (8.54 g, 39.2 mmol) was theņ added and stining was continued for 2 days, On the 3rf day, another portion of Boc20 (2.85 g, 13.1 mmol) was added and the reaction mixture stirred an additional day. Acetonitrile was removed under reduced pressure and the residue was partitioned between H2O and Et20.Step 3 [0180] 1-Aminocyclopropanecarboxylic acid (2.64 g, 26.1 mmol) and tetramethylammomum hydroxide (2.38 g, 26.1 mmol) were added to acetonitrile (150 mL). The reaction mixtux became homogeneous after stining at room temperature for about an honr. B0CO2 (8.54 g, 39.2 mmol) was added and the mixture was stirred for 2 days, 2.85 g, 13.1 mmol). Acetonitrile was removed under reduced pressure and H2O and Et20.

The aqueous layer was washed with Et20 and then acidified with solid citric acid to pH ~3. The aqueous solution was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO^)3 and the EtOAc was removed under reduced pressure to give 1 -tert-butoxycarbonylaminocyclopropanecaxboxylic acid as a white solid (2.32 g) which was used in the next step without further purification. 60The aqueous layer was washed with Et20 and then acidified with solid citric acid to pH ~ 3. The aqueous solution was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4) 3 and the EtOAc was removed under reduced pressure to give 1-tert-butoxycarbonylaminocyclopropanecaxboxylic acid as a white solid (2.32 g) which was used in the next step without further purification. 60

Step 4 [0181] To a solution of l-iert-butoxycarbonylamiiiocyclopropanecarboxylic acid (2.32 g, 11.5 mmnl) in CH2CI2 (25 mL) at 0 °C was added A(0-dmrethylhydroxylamine hydrochloride (1.24 g, 12,7 mmol), triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7 mmol). The reaction mixtuie was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and tlien partitioned between Et2Ū and water. The water layer was extracted with Et20. The combined organic layer was washed with brine, dried (ISLbSCb), and concentrated nnder reducedpressure to yield [1 -(methoxy-methyl-carbamoyl)-cyclopropyI]carbainic acid iert-b\ity\ ester which was used in the next step rvithout fnrther purificatiomStep 4 To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH 2 Cl 2 (25 mL) at 0 ° C was added A (0-dmrethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol). triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7 mmol) The reaction mixture was stirred at room temperature for 4 h. Et al., <RTI ID = 0.0> Et2O-Carblopoyl-CyclopropyI] carbainic </RTI> acid iert-b \ t which was used in the next step rvithout fnrther purificatiom

Step 5 [0182] To a 0.05 M solution of [l-(methoxymethyl-carbamoyl)cyclopropyl]carbamic acid iert-butyl ester in EtzO (80 mL, 4.0 mmol) at room temperature was added dropwise lithium aliEninumhydiide (1.0 M in EtaO, 5 mL, 5.0 mmol). The reaction mixture was stiired for another 20 min and then quenched vrith 6 mL of a solution of KHSO4 in water. The layers we separated and the aqueous layer was extracted with Et?0. The combined organic layers were v/ashed with 1 N HC1, saturated NaHCCb, and brine, dried (NaļSOf), and concentrated to yield (1 -fonnylcyclopropyl)carbamic acid ?e7'i-butyl ester as a colorless oil (393 mg) which was used immediately in the next step vvithout further purification.Step 5 To a 0.05 M solution of [1- (methoxymethylcarbamoyl) cyclopropyl] carbamic acid tert-butyl ester in Et 2 O (80 mL, 4.0 mmol) at room temperature was added dropwise lithium aliEninumhydide (1.0 M in EtaO). 5 mL, 5.0 mmol). The reaction mixture was stirred for another 20 min and then quenched by 6 mL of a solution of KHSO4 in water. The layers were extracted with Et? 0. 1N HCl, saturated NaHCO3, and brine, dried (NaSO4), and concentrated to yield (1-methylcyclopropyl) carbamic acid e7-butyl ester as a colorless oil (393mg) which was used immediately in the next step vvithout further purification.

Step 6 [0183] To a solution of (l-formylcyclopropyl)carbamic acid ieri-butyl ester (393 mg, 2.12 mmol) in CH2CĻ (4 mL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol), and cyclopropyl isocyanide (142 mg, 2.12 mmol). The reaction mixture was stirred oyemight at room temperature and then concentrated under reduced pressure to yield crude acetic acid (1-iert-butoxycarbonylaminocyclopropyl)cyclopropylcarbamoyl metbyl ester v/hichv/as used in the next step without further purification.Step 6 To a solution of (1-formylcyclopropyl) carbamic acid N-butyl ester (393 mg, 2.12 mmol) in CH 2 Cl 2 (4 mL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol), and cyclopropyl isocyanide (142 mg, 2.12 mmol). (1-tert-Butoxycarbonylaminocyclopropyl) cyclopropylcarbamoyl methyl ester v / hichv / as used in the next step without further purification.

Step 7 [0184] To a solution of the acetic acid (l4ertLutoxycarbonylaminocyclopropyl)-cyclopropylcarbamoyl methyl ester in MeOH (5 mL) was added 10% NaOH (1 mL). The reaction mixture was stirred at room temperature for 2 h and then acidified with 2.5N HC1 to pH 7. The solution was extracted witb EtOAc, washed with brine, dried (NaīSCh), and concentrated under reduced pressure to yield [l-(cyclopropylcarbamoylbydroxymethyl)cyclopropyl]- 61 61LV 13669 carbaroic acid tert-butyl ester as a yellow oil which was used ia the next step without forther purification.Step 7 To a solution of the acetic acid (14ertLutoxycarbonylaminocyclopropyl) -cyclopropylcarbamoyl methyl ester in MeOH (5 mL) was added 10% NaOH (1 mL). The solution was EtOAc, washed with brine, dried (NaClCh), and concentrated under reduced pressure to yield [l- (cyclopropylcarbamoylbydroxymethyl)] ) cyclopropyl] - 61 61LV 13669 carbaroic acid tert-butyl ester as a yellow oil which was used in the next step without forther purification.

Step 8 [0185] A solution of [ 1 -(cycIopropylcarbamoyUrydroxymethyl)cyclopropyl] carbamic acid teri-butyl ester in CH2CI2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction mkture was concentrated and chased with toluene to yield 2-(l -aminocyclopropyl)-A-cyclopiOpyl-2-hydroxyacetamide, [0186] Proceeding as described in Steps 3-8 above but substituting l-axninocyclopropane-carboxyIic acid with l-aminocyclohexanecarboxylic acid provided 2-(l-aminocyclohexyl)-7A cyclopropyl-2-hydroxyacetamide.Step 8 A solution of [1 - (cyclopropylcarbamoyUrydroxymethyl) cyclopropyl] carbamic acid tert-butyl ester in CH 2 Cl 2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction was concentrated and chased with toluene to yield 2- (1-Aminocyclopropyl) -A-cyclopropyl-2-hydroxyacetamide, Proceedings as described in Steps 3-8 above but substituting l-axninocyclopropane-carboxyIic acid with l- aminocyclohexanecarboxylic acid provided 2- (1-aminocyclohexyl) -7A cyclopropyl-2-hydroxyacetamide.

Reference FReference F

Synthesis of 3-amino-iV'-cyciopropyl-2-hydroxy-3-methylbutyramideSynthesis of 3-amino-N'-cyclopropyl-2-hydroxy-3-methylbutyramide

Step 1 [0187] To a solution of (2'hydxoxy-l;l-dmiethylethyl)-caxbaniic acid iert-\M\y\ ester (284 mg, 1.5 mmol) in CH2CI2 (5 mL) was added at 0 °C Dess-Martin periodane (763 mg, 1.8 mmol). After 1.5 h, a solution of 0.26M ^282(¼ in saturated NaHC03 (6 mL) was added and the resulting mixtuie was stirred for 15 min. The layers were separated and the aqueous layer was extractedwith CH2CI2, The combined organic layers were diied (Na2S04) and concentrated to yield (l,l-dfonethyl-2-oxo-ethyl)carbamic acid tertAmty\ ester as awhite solid whichwas used in the next step without fiīrther purification.Step 1 To a solution of (2'hydxoxy-1; 1-diethylethyl) -caxbaniic acid ester (284 mg, 1.5 mmol) in CH 2 Cl 2 (5 mL) was added at 0 ° C. Dess-Martin periodic (763 mg, 1.8 mmol). After 1.5 h, a solution of 0.26M ^ 282 (¼ in saturated NaHCO3 (6 mL) was added and the resulting layer was extracted with CH2Cl2, The combined organic layers were diied (Na2SO4) and concentrated to yield (1,1-dfonethyl-2-oxo-ethyl) carbamic acid tertAmty ester as awhite solid which is used in the next step without fiery purification.

Step 2 [0188] To a solution of (l,l-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester in CH2CI2 was added acetic acid (180 mg, 0.172 mL, 3.0 mmol) and cyclopropyl isocyanide (101 mg, 1.5 romol). The reaction mixture was stirred overoight at room temperature and then concentrated to yield cmde acetic acid 2-fe77-butoxycarbonylamino-l-cyclopropylcarbamoyl-2-methylpropyl ester which was used in the next step without further purification. 62Step 2 To a solution of (1,1-dimethyl-2-oxo-ethyl) -carbamic acid tert-butyl ester in CH 2 Cl 2 was added acetic acid (180 mg, 0.172 mL, 3.0 mmol) and cyclopropyl isocyanide (101 mg, 1.5 romol). Acetylic acid 2-fluoro-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester which was used in the next step without further purification. 62

Step 3 [0189] To a solution of acetic acid 2-iert-butoxycarbonylamino-l-cyclopropylcafbamoyl-2-methylpropyl ester in MeOH (10 mL) was added 10% NaOH (1.5 mL), The reaction mixture was stirred at room temperature for 3 h and then acidified witb 1N Hydrocbloric acid to pH 7. The reaction inixture was extracted with EtOAc. The organic layer v/as diied (Na2S04) concentrated to yield (2-cyclopropylcarbarooyl-2-hydroxy-l J-dimethyle%l)-carbarnic acid /erf-butyl ester which was nsed in the next step v/ithout further purification.Step 3 To a solution of acetic acid 2-tert-butoxycarbonylamino-1-cyclopropylcafbamoyl-2-methylpropyl ester in MeOH (10 mL) was added 10% NaOH (1.5 mL). 3 h and then acidified 1N Hydrocbloric acid to pH 7. The reaction inixture was extracted with EtOAc. The organic layer (s) (Na 2 SO 4) concentrated to yield (2-cyclopropylcarbarooyl-2-hydroxy-1 J-dimethyl-l) -carbarnic acid / erf-butyl ester which was nsed in the next step v / ithout further purification.

Step 4 [0190] A solution of (2-cyclopropylcaxbamoyl-2-hydroxy-l, l-dimethylethyl)-carbamic acid iert-butyl ester in CH2CI2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 h, The reaction mixture was then concentrated and chased with toluene to yield 3-amino-TV-cyclopropyl-2'hydroxy-3 -methyibutyrainide.Step 4 A solution of (2-cyclopropylcaxbamoyl-2-hydroxy-1,1-dimethylethyl) -carbamic acid tert-butyl ester in CH2Cl2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 h The reaction mixture was then concentrated and chased with toluene to yield 3-amino-TV-cyclopropyl-2'hydroxy-3-methylbutyride.

Reference GReference G

Syntbesis of 3-amino-iV-benzyl-2-hydroxy-3-methylbutyrainideSyntbesis of 3-amino-N-benzyl-2-hydroxy-3-methylbutyrainide

?H H? H H

[0191] 3-Ajnino-iV-benzyl-2-hydroxy-3-metliylbutyTamide was made by the procedure described for 3-amino-Ar-cyclopropyl-2-hydroxy-3-methylbutyramideby substituting cyclopropyl isocyam.de with benzyl isocyanide.3-Amino-N-benzyl-2-hydroxy-3-methyl-butyl-3-amino-Ar-cyclopropyl-2-hydroxy-3-methyl-butyramide-substitution cyclopropyl isocyam.de with benzyl isocyanide.

Example 1Example 1

Synthesis of2-oxo-3(.5)-{3-(pyridm-3-ylmethahesulfonyl)-2(R)-[2,2324rifluoro-l(1S)-(4-fluorophenyl)ethylanmio]-propionylan±io}liexanoic acid cyclopropylaxoideSynthesis of 2-oxo-3 (.5) - {3- (pyrid-3-ylmethesulfonyl) -2 (R) - [2,23,2-trifluoro-1 (1S) - (4-fluorophenyl) ethylanmio] propionyl} acyl} acid cyclopropylaxoide

63 63LV 1366963 63LV 13669

Step 1 [0192] Catecholborane (19.4 mL, 182 mmol) in dicblorometbane (15 mL) was added to a dichloromethane solution of ^-metliļd CBS oxazaborolidine (13 mL, 13 mmol) and 2,2,2,4’-tetrafluoroacetopheone (18.2 mL, 130.l3mmol) dropv/ise at -78 °C in 30 min. The reaction mixtuie was stinred at -78 °C ovemight. The reaction mixture was quenched with 4N HC1 (13 mL) in dioxane at -78 °C, waimed up to room temperature and the solvent v/as removed nnder reducedpressnre. 10% NaHSCL solution (200 mL) was added to concentrate and the aqueous layer was exfractedby hexane. The organic layer was washed by water and dried with MgSCL Solvent was removed under the reduced pressure to give.2,2,2-tdfluoro-l(7?)-(4-fluorophenyl)-ethanol (20 g) as colorless oil (90% e.e.).Step 1 Catecholborane (19.4 mL, 182 mmol) in dicllorometbane (15 mL) was added to dichloromethane solution of β-methyl CBS oxazaborolidines (13 mL, 13 mmol) and 2,2,2,4'-tetrafluoroacetopheone ( 18.2 mL, 130.13 mmol) dropv / self at -78 ° C in 30 min. The reaction mixtuie was stinred at -78 ° C ovemight. The reaction mixture was quenched with 4N HCl (13 mL) in dioxane at -78 ° C, and the solvent was removed. 10% NaHSCL solution (200 mL) was added to the aqueous layer was exfractedby hexane. The organic layer was washed with water and dried with MgSCL Solvent was removed under the reduced pressure to give.2,2,2-tlufluoro-1 (7?) - (4-fluorophenyl) -ethanol (20 g) as colorless oil ( 90% ee).

Step 2 [0193] NaH (11.87 g, 296.7mmol) was added to Et20 (700 mL) at 0 °C under N2 followed by addition of an Et20 solution of 2,2,2-tzifluoro-l(f?)-(4-fluorophenyl)ethanol (44.3g, 228.2 mmol). The reaction mixture was siirred for 10 min at 0 °C then Ih at room temperature. Tiiiluoromethanesulfonyl chloride (50 g, 296.7 mmol) in Et20 v/as added at 0 °C under N2 and the reaction mixtuie was stirred 10 min at 0 °C then 3h at room temperature. The solvent was removed under the reduced pressure and H20 (100 mL) was added slowly. The aqueous layer was extracted hy hexane and the combined organic layer v/as diied over MgSCĻ The solvent v/as removed under the reduced pressure to give trifluoromethanesulfonic acid 2,2,2-trifluoro-l(K)-(4-fluorophenyl)ethyl ester (70 g) as colorless oil.Step 2 NaH (11.87 g, 296.7 mmol) was added to Et 2 O (700 mL) at 0 ° C under N 2 followed by addition of an Et 2 O solution of 2,2,2-tzifluoro-1 (f?) - ( 4-Fluorophenyl) ethanol (44.3g, 228.2 mmol). The reaction mixture was transferred for 10 min at 0 ° C then Ih at room temperature. Ethyl fluoromethane sulfonyl chloride (50 g, 296.7 mmol) in Et 2 O / ml added at 0 ° C under reaction mixture was stirred for 10 min at 0 ° C then 3h at room temperature. The solvent was removed under reduced pressure and H 2 O (100 mL) was added slowly. The solvent was dissolved in MgSO4, and the solvent was removed to give trifluoromethanesulfonic acid 2,2,2-trifluoro-1 (K) - (4-fluorophenyl) ethyl ester (70 g) as colorless oil.

Step 3 [0194] 2(i?)-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6mmol) v/as dissolved in CH2C12 and DIPEA (112 mL, 643.8mmol) was added and the reaction mixture v/as stirred for 10 min at room temperature. Trifluoromethanesulfonic acid2,2,2-tiifluoro-l(f?)-(4-fluorophenyl)ethyl ester (70 g, 214.6mmol) in CH2C12 ^as added and the reaction mixture was stirred ovemight at room temperature. Solvent was removed under the reduced pressure and the residue was dissolved in Et20 and v/ashed with IN HC1, brine and dried over MgSO*. Solvent was removed give 2(E)-[2,2,2-trifluoro-l(£)-(4-fluorophenyl)ethylanxmo]-3-tritylsulfanylpropionic acid (90 g) as a yellow solid. 64Step 3 2 (i) - Amino-3-tritylsulfanylpropionic acid (78 g, 214.6 mmol) dissolved in CH 2 Cl 2 and DIPEA (112 mL, 643.8 mmol) was added to the reaction mixture. 10 min at room temperature. Trifluoromethanesulfonic acid2,2,2-thiofluoro-1 (f) - (4-fluorophenyl) ethyl ester (70 g, 214.6 mmol) in CH 2 Cl 2 as a reaction mixture. Solvent was removed in Et 2 O and v / ash with IN HCl, brine and dried over MgSO *. Solvent was removed give 2 (E) - [2,2,2-trifluoro-1 (E) - (4-fluorophenyl) ethylanxo] -3-tritylsulfanylpropionic acid (90 g) as a yellow solid. 64

Step 4 ' [0195] 2(f?)-[2,2,2-trifiuoiO4(i5)-(4-fluorophenyl)ethylamino]-34ritylsulfanylpropionic acid ( 5.4 g, 10 mmol) was dissolved in CH2CI2 and TFA (3,1 mL, 40 mmol) was added at 0 °C under N2. EtaSiH (3.2 mL, 20mmol) v/as added at 0 °C under N2 and the reaction mixtuxe was vvanned up to room temperature. After stirring for 2 h, the solvent v/as removed under the reduced pressure and the residue v/as dissolved in lNNaOH (120 roL). The aqueous layer was extracted with hexane. To the aqueous solution dioxane (120 mL), 3-picolyl chloride hydrochloride (1.97g, 12 mmol), andtiis(2-carboxyethyl)phosphinehydrochloride (280 mg, 1 ramol)we added. The reaction mixture was stiired at room temperature ovemight. Dioxane v/as removed under the reduced pressure. The aaueous solution v/as adjusted to pH 3 and vvas extracted vvith ethyl acetate. The combined organic extracts were dried over MgSCL, filtered and concentrated under the reduced pressure to give 3-(pyridin-3’ylmethanesulfanyl)-2(i?)-[2,2,2-trifluoro-l(iS)-(4-fluorophenyl)-ethylamino]propionic acid which was used in the next step vvithout furtlier purification.Step 4 '2 (f) - [2,2,2-trifluoro-4 (15) - (4-fluorophenyl) ethylamino] -34-sulphanylpropionic acid (5.4 g, 10 mmol) was dissolved in CH 2 Cl 2 and TFA (3 g). 1 mL, 40 mmol) was added at 0 ° C under N2. EtaSiH (3.2 mL, 20 mmol) was added at 0 ° C and the reaction was mixed with room temperature. After stirring for 2 h, the solvent was removed in 1NNaOH (120 roL). The aqueous layer was extracted with hexane. To the aqueous solution of dioxane (120 mL), 3-picolyl chloride hydrochloride (1.97 g, 12 mmol), andtis (2-carboxyethyl) phosphinehydrochloride (280 mg, 1 ramol) we added. The reaction mixture was at the room temperature ovemight. Dioxane v / as removed under the reduced pressure. The solution was adjusted to pH 3 and vvith ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 3- (pyridin-3'ylmethanesulfanyl) -2 (i) - [2,2,2-trifluoro-1 (iS) - (4) -fluorophenyl) -ethylamino] propionic acid which was used in the next step vvithout furtlier purification.

Step 5 [0196] To^ a solution of 3-(pyridm-3-ylmethanesulfanyl)-2(l?)-[2,2,2-irifluoro-l(ij)-(4-fluorophenyl)-ethylamino]propioEdc acid iņmethanol (10 mL), an aqueous solution of ΟΧΟΝΕ® (4.68g, 15 rninol in 10 mL H20) was added, The reaction mixtuxe vvas stiired at room temperature. After 2 h. solvent v/as removed under reduced pressure. The aqueous layer vvas extracted vvith ethyl acetate and the combined organic extracts were v/as washed v/ith brine and dried vvith MgS04 and filtered The filtrate was concentrated under the reduced pressure to give 3-(pyridm-3-}lme&amp;anesulfonyl)-2-(A)[2,2,2-trifluoro-l(jS)-(4-fluorophenyl)ethylainio.o] propionic acid v/hich v/as used in the next step v/ithout furtlier purification.Step 5: To a solution of 3- (pyrid-3-ylmethanesulfanyl) -2 (1H) - [2,2,2-irifluoro-1 (ij) - (4-fluorophenyl) -ethylamino] propioEdc acid ethanol (10 mL), an aqueous solution of ΟΧΟΝΕ® (4.68 g, rninol in 10 mL H 2 O) was added. After 2 h. solvent under reduced pressure. The aqueous layer was dried and dried with MgSO 4 and filtered The filtrate was concentrated under reduced pressure to give 3- (pyrid-3-} lme &amp; anesulfonyl) -2- (A) [2,2,2-trifluoro-1 (jS) - (4-fluorophenyl) ethylainio.o] propionic acid v / hich v / as used in the next step v / ithout furtlier purification.

Step 6 [0197] Amixtureof3-(pyTidm-3-ylmethanesulfonyl)-2-(l?)[2,2,2-tiifiuoro-l(iy)-(4·-finorophenyl)ethylamino] propionic acid (420 mg, 1 mmol), 3(i5)-amino-2-hydroxyhexanoic acid cyclopropylamide (186 mg, 1 mmol) prepared as described in PCT applicationpublication No. WO-02/18369 as compound xiii, HBTU (455 mg, 1.2 mmol), and NMM (0.44mL, 4 mmol) in acetonihile v/as stiired at room temperature ovemight. Sat. NH4CI (10 mL) and ethyl acetate (10 mL) were added and after 20 min the aqueous layer v/as extracted v/ith ethyl acetate. The combined organic extracts were vvashed v/ith brine and dried vvith MgS04, filtered and the filtrated was concentrated under the reduced pressure to give 2-hydxoxy-3(5)-{3-(pyri(lin-3- 65 65 LV 13669 ybnethanesulfonyl)-2(P)-[2,2,2-hifhioro-l(i5)-(4-fluoiophenyl)-ethylamino]propionylamino}-hexanoic acid cyclopropylamide whichwas used in the next step without further purification.Step 6 [0197] Amxtureof3- (pyridm-3-ylmethanesulfonyl) -2- (1?) [2,2,2-thiofluoro-1 (i?) - (4? -Finorophenyl) ethylamino] propionic acid (420 mg, 1 mmol), 3 (15) -amino-2-hydroxyhexanoic acid cyclopropylamide (186 mg, 1 mmol) prepared as described in PCT applicationpublication No. WO-02/18369 as compound xiii, HBTU (455mg, 1.2mmol), and NMM (0.44mL, 4mmol) in acetonitrile w / w at room temperature ovemight. Sat. NH 4 Cl (10 mL) and ethyl acetate (10 mL) were added after 20 min. The combined organic extracts were dried and dried by MgS04, filtered and concentrated by 2-hydxoxy-3 (5) - {3- (pyri (lin-3- 65 65 EN 13669) ybnethanesulfonyl) -2 (P) - [2,2,2-Hiphioro-1 (15) - (4-fluorophenyl) -ethylamino] propionylamino} -hexanoic acid cyclopropylamide which is used in the next step without further purification.

Step 7 [0198] To a solution of 2-hydioxy-3(6)-{3-(pyridm-3-y3rQethaiiesulfonyl)-2(i?)-[2,252-trifluoro-l(&lt;S)-(4-fhmrophenyl)ethyIammo]propionylarnino}hexanoicacidcyclopropylarnide (590 mg, 1 mmol) in' methylene chloride, DMP was added slowly. The reaction mixture was stkred at room temperature for 30 min and then a 0.26 M Na^SaOj in sat. NaHC03 was added. The reaction mixture was stirred for 20 min. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried overMgSOļ, filtered and concentiated to give 2-oxo-3(iS)-{3-(p yridin-3-ylmethmesulfonyl) ~2(ū)-[2,2,2-trifluoro-l (6)-(4-fluorophenyl)ethylamino]-propionylainino}hexanoic acid cyclopropylamide which was purified by flash column (2% MeOH-CHiCĻ) to give pure product as a yeliow solid. I0199] rH-NMR(DMSO-ds): δ 0.80(m, 12H), 2.02(m, 1H), 3.3-3.7(b, 3H), 4.00(m, 1H), 4.46(m. 1H), 4.79(m, 2H), 7.25(m, 2H), 7.50(m, 2Ή), 7.65(b, 1H), 7.72(d, 1H), 8.01(d,1H), 8.71(m, 3H). LC-MS: 587(M+1), 585, (M-l), 609(M+23).Step 7 To a solution of 2-Hydroxy-3 (6) - {3- (pyrid-3-ylmethylsulfonyl) -2 (R) - [2,252-trifluoro-l (&lt; S) - (4- fhmrophenyl) ethyammo] propionylarnino} hexanoicacidcyclopropylarnide (590 mg, 1 mmol) in 'methylene chloride, DMP was added slowly. The reaction mixture was stirred at room temperature for 30 min and then at 0.26 M Na ^OO in sat. NaHC03 was added. The reaction mixture was mixed for 20 min. 2-Oxo-3 (iS) - {3- (pyridin-3-ylmethmesulfonyl) ~ 2 (ū) - [2] 2,2-Trifluoro-1- (6) - (4-fluorophenyl) ethylamino] propionyl} hexanoic acid cyclopropylamide which was purified by flash column (2% MeOH-CH 2 Cl 2) to give pure product as a yeliow solid. 1 H NMR (DMSO-d 6): δ 0.80 (m, 12H), 2.02 (m, 1H), 3.3-3.7 (b, 3H), 4.00 (m, 1H), 4.46 (m. 1H), 4.79 (m, 2H), 7.25 (m, 2H), 7.50 (m, 2Ή), 7.65 (b, 1H), 7.72 (d, 1H), 8.01 (d, 1H), 8.71 (m, 3H). LC-MS: 587 (M + 1), 585, (M-1), 609 (M + 23).

[0200] Proceeding as described above but subsiituiing 3-picolyl chloride with cyclopropylmethyl bromide provided 2-oxo-3(6)-{3-(cyclopropylmethanesulfonyl)-2(.S)-[2,2,2-trifluoro-1 (5)-(4-fluorophenyl)ethylamino]-propionylaimno}hexanoic acid cyclopropylaroide (compound 1). ^-NMRpMSO-dg): δ 0.32-0.41 (m, 2H), 0.53-0.67 (m, 6H), 0.8l(t, J=7.2Hz, 3H), 1.06-1.38 (m, 4H), 1.52-1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, 1=2.8¾ J=14.SHz, 1H), 3.19 (dd, J=8Hz, J=14Hz, 1H), 3.28-3.50 (m, 3H), 3.82-3.88 (m, 1H), 4.37 (quint, 1=7.6¾ 1H), 4.70-4.76 (m, 1H), 7.22 (t, 1=8.4¾ 2H), 7.43 (dd, 1=5.6¾ 1=8.4¾ 2H), 8.51 (d, 1=7.2¾ 1H), 8.73 (d, 1=5.2¾ 1H), LC-MS: 550(M+1), 548, (M-l). 662-Oxo-3 (6) - {3- (cyclopropylmethanesulfonyl) -2 (.S) - [2,2,2-trifluoro-1 (Proc.) As described above 5) - (4-Fluorophenyl) ethylamino] -propionylamino} hexanoic acid cyclopropylaroide (compound 1). N-NMRpMSO-dg): δ 0.32-0.41 (m, 2H), 0.53-0.67 (m, 6H), 0.8l (t, J = 7.2Hz, 3H), 1.06-1.38 (m, 4H), 1.52- 1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, 1 = 2.8¾ J = 14.SHz, 1H), 3.19 (dd, J = 8Hz, J = 14Hz, 1H), 3.28- 3.50 (m, 3H), 3.82-3.88 (m, 1H), 4.37 (quint, = 7.6µl 1H), 4.70-4.76 (m, 1H), 7.22 (t, 1 = 8.4µ2H), 7.43 (dd , 1 = 5.6¾ 1 = 8.4¾ 2H), 8.51 (d, 1 = 7.2¾ 1H), 8.73 (d, 1 = 5.2¾ 1H), LC-MS: 550 (M + 1), 548, (MH +) . 66

Example 2Example 2

Synthesis of2-oxo-3 (6)-3-[2(J?)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridyl-3-ylmethanesulfonyl)propionylamino]pentanoic acid cyclopropylamideSynthesis of 2-oxo-3 (6) -3- [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridyl-3-ylmethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide

Step 1 {0201] To a -7S °C methylene chloride solution (75 mL) of 2,2,3,3,3-pentafluoropropan-l-ol (1.5 g, 10.0 mmol) and DEPEA (6.1 mL, 35.0 mmol) v/as added triftic aohydiide (1.78 mL, 10.5 mmol). After 2.5 h, S-tiitylcysteine v/as added ali ai once and the reaction mixture \vas stirred at 0 °C for 80 min. The reaction mixture v/as stirred at RT for 18 h and then concentrated on the rotovap. Ethyl acetate was added and the reaction mixture was washed vvith 1N HC1. The organic layer v/as diied over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chiomatography (3 hexanes/l ethyl acetate+1 % acetic acid) to provide 2(E)-(2,2,3,3,3-pentailuoropropylamino)-3-tdtylsulfanylpropionic acid (3.29 g).Step 1 {0201} To a -7S ° C methylene chloride solution (75 mL) of 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DEPEA (6.1 mL, 35.0 mmol) added triftic aohydide (1.78 mL, 10.5 mmol). After 2.5 h, S-thesis on the next step at 0 ° C for 80 min. The reaction mixture is at RT for 18 h and then concentrated on the rotovap. Ethyl acetate was added and the reaction mixture was washed vvith 1N HCl. The organic layer is magnesium sulfate, filtered and concentrated. (3 hexanes / ethyl acetate + 1% acetic acid) to provide 2 (E) - (2,2,3,3,3-pentyloropropylamino) -3-tdtylsulfanylpropionic acid (3.29 g) .

Step 2 [0202] To a methylene chloride solution (15 mL) of 2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid (1.05 g, 2.12 mmol) was added TFA (0.653 mL, 8.48 mmol) followed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then concentrated on the rotovap. To the residue was added 2N NaOH solution (20 mL) and the reaction mixture was extracted v/ith hexanes. To the NaOH layer was added tiis(2-carboxytriethyl)phosphine hydrochloride (60 mg) follovved by 3-picolylchloiide hydrochloride (348 mg, 2.12 mmol). After 1.5 b, the reaction mrsture was acidified with conc. HC1 to ~pH=4 and extracted v/ith ethyl acetate. The organic layer was dried and concentrated to give 2(2?)-(2,2,3,3,3-pentaflnoropropylamiiio)-3-(pyridin-3-ylmethanesufanyl)propionic acid (530 mg). 67 67LV 13669Step 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3-tritylsulfanylpropionic acid (1.05 g, 2.12 mmol) was added to TFA (0.653). mL, 8.48 mmol) followed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was mixed for 1.5 h at room temperature and then concentrated on the rotovap. The residue was added 2N NaOH solution (20 mL) and the reaction mixture was extracted in hexanes. The NaOH layer was added to thi (2-carboxytriethyl) phosphine hydrochloride (60 mg) follovved by 3-picolylchloiide hydrochloride (348 mg, 2.12 mmol). After 1.5 b, the reaction mrsture was acidified with conc. HCl to ~ pH = 4 and extracted v / ith ethyl acetate. 2 (2) - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionic acid (530 mg). 67 67LV 13669

Step3 [0203] To amethylene chloride solution of 2(5)-(2,2,3,3,3-pentafluoropiopylainiao)-3-(pyridin-3-ylmetlianesufanyl)piopionic aoid (151 mg, 0.44 mmol), 3(«S)-ammo-2-hydroxypentanoic acid cyclopropylamide hydrochloride (92 mg, 0.44 mmol), EDC (102 mg, 0.66 mmol), and HOBt liydrate (71 mg, 0.53 mmol) was added iV-methylmoipholine (0.194 mL, 1.76 mmol). The reaction mbcture was stiired for 2 h and then diluted with ethyl acetate and washed with sodium bicarbonate solution. Concentration of the organic layer gavē 2-hydroxy-3(6)-(2(5)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfanyl)propionylamino]pentanoic acid cyclopropylamide (170 mg).Step3 To 2: (5) - (2,2,3,3,3-pentafluoropyropylano) -3- (pyridin-3-ylmethanesulfonyl) pyrophenic acid (151 mg, 0.44 mmol). S) -ammo-2-hydroxypentanoic acid cyclopropylamide hydrochloride (92 mg, 0.44 mmol), EDC (102 mg, 0.66 mmol), and HOBt liydrate (71 mg, 0.53 mmol) was added as N-methylmoiphol (0.194 mL, 1.76 mmol) . The reaction mbcture was stimulated for 2 h and then diluted with ethyl acetate and washed with sodium bicarbonate solution. 2-hydroxy-3 (6) - (2 (5) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionylamino] pentanoic acid cyclopropylamide Concentration of the organic layer 170 mg).

Step 4 [0204] To anNMP solution of2-hydroxy-3(iS)-[2(5)-(2,2,3,3;3-pentafluoropropylainino)-3-(pyridin-3-ylmethaaesulfanyl)propionylamiQo]pentanoic acid cyclopropylamide (170 mg, 0.34 mmol) was added an aqueous solution of ΟΧΟΝΕ® (209 mg, 0.34 mmol). After 2 h, more ΟΧΟΝΕ® (105 mg, 0.17 mmol) was added with additional waterplus some methanol. After an additional lh 40 min, the reaction mixture was diluted with ethyl acetate and washed with water. Concentration of the organic layer provided 2-hydroxy-3(5)-[2(R)-(2,2,3,3,3-pentafluoropropyl-amino)-3-{pyiidin-3-ylmethylsulfonyl)propionylamino]pentanoic acid cyclopropylamide (176 mg).Step 4 To anNMP solution of 2-hydroxy-3 (1S) - [2 (5) - (2,2,3,3; 3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionyl] pentanoic acid cyclopropylamide (170 mg, 0.34 mmol) was added an aqueous solution of of® (209 mg, 0.34 mmol). After 2 h, more ΟΧΟΝΕ ® (105 mg, 0.17 mmol) was added with additional waterplus some methanol. After an additional lh 40 min, the reaction mixture was diluted with ethyl acetate and washed with water. 2-hydroxy-3 (5) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethylsulfonyl) propionylamino] pentanoic acid cyclopropylamide (176 mg).

Step 5 [0205] To a heterogeneous mixture of 2-hydroxy-3(d)-[2(5)-(2,2,3,3,3 -pentafhioropropyl-amino)-3-(pyridin-3-yhnethanesulfonyl)propionylaiiiino]pentanoic acid cyclopropylamide (176 mg, 0.33 mmol) in methylene chloride was added Dess-Martin periodinane (183 mg, 0.43 mmol). The reaction mixture became more heterogeneous after a couple of minūtes. After 3 h, acetonitrile (3 mL) v/as added follov/ed by NMP (6 mL) to give a homogeneous reaction, Additional Dess-Martin periodinane was added at this time (100 mg). After an additional 70 . min of stiiring, the reaction mixtuxe was diluted vrith ethyl acetate and washed rvith sodium bicarbonate solution. The organic layer was separated and concentrated. Flash chromatography (95% methylene chloride/ 5% methanol) of the residue provided a solid which was suspended in a 1:1 IPA/ethanol miīiure and allovved to evaporate to dyness to provide 2-oxo-3(i5)-3-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridyl-3-yhiethanesulfonyl)propionylamino]pentanoic acid cyclopropylarnide(87 mg). 68Step 5 To a heterogeneous mixture of 2-hydroxy-3 (d) - [2 (5) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propionyl]] pentanoic acid cyclopropylamide (176 mg, 0.33 mmol) in methylene chloride was added Dess-Martin periodinane (183 mg, 0.43 mmol). The reaction mixture became more heterogeneous after a couple of minutes. After 3 h, acetonitrile (3 mL) was added by NMP (6 mL) to give a homogeneous reaction, Additional Dess-Martin periodinane (100 mg). After an additional 70. min of ringing, the reaction mixtux was diluted vrith ethyl acetate and washed rvith sodium bicarbonate solution. The organic layer was separated and concentrated. Flash chromatography (95% methylene chloride / 5% methanol) of the residue provided by a 1: 1 IPA / ethanol mole and allovved to evaporate to provide 2-oxo-3 (i5) -3- [ 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridyl-3-ylethanesulfonyl) propionylamino] pentanoic acid cyclopropylarnide (87 mg). 68

Ex'2rnple 3Ex'2rnple 3

Synthesis ofM-(l-cyclopropylaniinooxalylcyclopropyl)-3-cyclopiOpylmethanesulibnyl-2(i?)-[2,2,2-trifluoro-1 (i5)-(4-fmorophenyl)ethylanrino]propion&amp;mideSynthesis ofM- (1-cyclopropylaninoxalylcyclopropyl) -3-cyclopropylmethanesulibnyl-2 (R) - [2,2,2-trifluoro-1 (15) - (4-fluorophenyl) ethylanrino] propion &amp; mide

rS02rS02

Step 1 [0206] To asohitionof3-cyclopropyhnethanesulfanyl-2(ic)-[2,2,2-1rifluoro-l(i5)-(4-fluorophenyl)ethylamino]-propionic acid (148 mg, 0.42mmol), prepared as described in example Γ above, by substitutiag picolyl chloride vrith cyclopropylmethyl bromide, and 2-(l-amino-cyclopropyl)-Mcyclopropyl-2-hydroxyacetamide (108 mg, 0.63 mmcl) iniV-me{hylpynOlidme (6 mL) ai 0 °C was added NAr-diethy]propylamine (272 mg, 0.37 mL, 2.11 roinol), and HATU. The reaction mixture was stirred 4 hours ai rooin temperature. The reaction mistas was diluted vvith EtOAc and v/ashed with H2O. The organic layer was dried (Na2S04) and concentrated to yieldA-[l-(cyclopropylcarbamoyl-hydroxy-meihyl)cyclopropyl]-3-cyclopropylmethylsulfanyl-2-[2,2,2-tdfluoro-l-(4-fIuorophenyl)-eihylarnino]propionarnide which v/as converied to the title compound as described in Example 2, steps 4 and 5 above. MS (534.2 M+l, 532.1 M-l). . [0207] Follwing the procedure described in Example 3 above but substituting 2-(l-amino- cyclopropyl)-iV-cyclopropyl-2-hydroxyacetaEnide vvith 3-amino-iT-benzyl-2'hydioxy-3-methylbutyxamideprovidediV'-benzyl-3-{3-cyclopiOpyhnethanesulfonyl-2(i?)-[2,2,2-triiluoro-l(15}-(4-fluorophenyl)ethylamino]propionylamino}-3-methyl-2-oxo-butyTaniide. MS (586.3 M+l, 584.3 M-l). .Step 1 To azithionophen-3-cyclopropyhnethanesulfanyl-2 (ic) - [2,2,2-1-trifluoro-1- (15) - (4-fluorophenyl) ethylamino] -propionic acid (148 mg, 0.42 mmol), prepared as described in example Γ above, by substitution of picolyl chloride vrith cyclopropylmethyl bromide, and 2- (1-aminocyclopropyl) -Mycyclopropyl-2-hydroxyacetamide (108 mg, 0.63 mmcl) iniV-Me {shampoo Olidme (6 mL) α 0 ° C was added NAr-diethy] propylamine (272 mg, 0.37 mL, 2.11 roinol), and HATU. 4 hours ai rooin temperature. EtOAc and v / ashed with H2O. The organic layer was dried (Na2SO4) and concentrated to yield A- [1- (cyclopropylcarbamoyl-hydroxy-methyl) -cyclopropyl] -3-cyclopropylmethylsulfanyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -yl] -carbamide ] propionarnide which v / as convertible to the title compound as described in Example 2, steps 4 and 5 above. MS (534.2 M + 1, 532.1 M-1). . Example 3 above but substituting 2- (1-Amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetaEnide vvith 3-amino-iT-benzyl-2'hydroxy-3-methylbutyxamideprovidedV-benzyl- 3- {3-Cyclopropyl-pyranethanesulfonyl-2 (R) - [2,2,2-trifluoro-1- (15} - (4-fluoro-phenyl) -ethylamino] -propionylamino} -3-methyl-2-oxo-butythane. MS (586.3) M + 1, 584.3 M).

[0208] FoUwing the procedure described in Example 3 above but substituting 2-(l-amino-cyclopropyl)-iV-cyclppropyl-2-hydroxyacetanxide with 3 -amino-N-benzyl-2-hydroxy-3-methylbutyramide and 2(i?)-[2,2,2-trifluoro-l(1S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid with 2(i?)-[2,2,2-trifluoro-l(it)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid provided jV-benzyl-3-{3-cyclopropyhnethaiīesulfonyl-2(7?)-[2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethylamino]propionylamino}-3-me1hyl-2-oxo-butyramide. N-Benzyl-3-{3-cyclopropyhnetlianesulfonyl-2-[2,2,2-trifluoro-l-(4-fluoro-phenyl)-ethylainino]-propionylamino}-3-methyI-2-oxo-butyramideMS (586.1 M+l, 584.1 M-l). 69 69LV 13669 [0209] Follvdng the procedure described in Example 3 above but substituting 2-(l-amino-cyclopropyl)-Ar-cyclopropyl-2-hydroxyacetamide with 3—amino-iV-cydopxopyl-2-hydxoxy-3 -methylbutyrainide providediV'~cyclopropyI-3-{3-cycIopropylmethanesulfbnyl-2(.£)-[2,2,2-trifluoro-l(£)-(4-fluoiophenyl)ethylamino]propionylanīmo}-3-methyl-2-oxo-butyrainide. MS (536,0 M+l, 534.2 M-l).Example 2 above but substituting 2- (1-Amino-cyclopropyl) -N-cyclppropyl-2-hydroxyacetanxide with 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide and 2 (i) ?) - [2,2,2-Trifluoro-1 (1S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropionic acid with 2 (R) - [2,2,2-trifluoro-l (s) - (4-Fluorophenyl) ethylamino] -3-tritylsulfanylpropionic acid provided N-benzyl-3- {3-cyclopropylmethane sulfonyl-2 (7?) - [2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethylamino ] propionylamino} -3-methyl-2-oxo-butyramide. N-Benzyl-3- {3-cyclopropylmethylenesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -ethyl] -amino] -propionylamino} -3-methy-2-oxo-butyramide (586.1 M +1.584.1 Ml). 69 69LV 13669 Follow-up procedure described in Example 2 above but substituting 2- (1-amino-cyclopropyl) -Arcyclopropyl-2-hydroxyacetamide with 3-amino-N-cydopopopyl-2-hydroxyoxy-3-methylbutyrain Cyclopropyl-3- {3-cyclopropylmethanesulfbnyl-2 (E) - [2,2,2-trifluoro-1 (E) - (4-fluoro-phenyl) -ethylamino] -propionylamino} -3-methyl-2-oxo-butyrenes . MS (536.0 M + 1, 534.2 M-1).

Example 4Example 4

Syntbesis of 3(iS)-[3-cyclopropylmethmesdfonyl-2(E)-(2,2,3,3,3-pentafluoropropylatniiio)- propionylamino]-2-oxo-pentanoic acid cyclopropylamideSyntbesis of 3 (1S) - [3-cyclopropylmethmesdfonyl-2 (E) - (2,2,3,3,3-pentafluoropropylthio) propionylamino] -2-oxo-pentanoic acid cyclopropylamide

Step 1 [0210] To a -78 °C dichiororaethane solution (75 mL) of 2,2,3,3,3-pentafluoropentan-1 -ol (1.5 g, 10,0 mmol) and DIPEA (6.3mL, 35.0 mmol) was added triiiic anhydride (1.78 mL, 10.5 mmol) dropwise. Afier 2h and 20roin, S-triĪyl cysteine was added to the reaction and siiiring continued for Ih and 15 min at °C and then 19 h ai room temperature. The reaction mbrture was concsntrated on the rotovap and the residne was subjected to ilash cbxoīnatograpliy (3:1, hexanes/ethy3 acetate with 1% acetic acid) to provide 2(i?)-(2,2,3,3,3-pentafluoropropylanmio)-3-tritylsnlfanylpropionic acid (3.29g).Step 1 To -78 ° C Dichiororaethane Solution (75 mL) of 2,2,3,3,3-pentafluoropentan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.3 mL, 35.0 mmol) ) was added trifilic anhydride (1.78 mL, 10.5 mmol) dropwise. Afier 2h and 20roin, S-triyl cysteine was added to the reaction and filtration continued for Ih and 15 min at room temperature. (3: 1, hexanes / ethy3 acetate with 1% acetic acid) to provide 2 (i?) - (2,2,3,3,3-) pentafluoropropylanimio) -3-trityl-trifluoro-propionic acid (3.29g).

Step 2 [0211] To a dichloromethane solution of 2(i?)-(2,2,3,3,3-pentafluoropropylamiao)-3-tiityl-sulfanylpropionic acid (1.05 g, 2.12 mmol) was added TFA (0.653 mL, 8.48 mmol) fo]lowed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stiired for Ih and 20 min at room temperature and then concentrated on the rotovap. To the residue was added 2N NaOH and hexanes. The mixtnre was shaken and the NaOH layer separated. To the NaOH iayer was added cyclopropylmethyl bromide (0.206 mL, 2.12 mmol). The reaction mixture was stirred for 17 h at room temperature and then acidified with 1N HC1 and the product extracted into ethylacetate. The ethyi acetate layer was washed vdthbrine, dzied overmagnesīum sulfate, 70 filtered and concentrated to provide 2(i$)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropyl-methanesnlfanyl)piopionic acid (428 mg).Step 2 Dichloromethane solution of 2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3-thiol sulfanylpropionic acid (1.05 g, 2.12 mmol) was added TFA (0.653 mL, 8.48 mmol) fo] lowed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stained for 20 min at room temperature and then concentrated on the rotovap. To the residue was added 2N NaOH and hexanes. The mixtnre was shaken and the NaOH layer separated. To the NaOH iayer was added cyclopropylmethyl bromide (0.206 mL, 2.12 mmol). The reaction mixture was mixed with 1N HCl and the product extracted into ethylacetate. 2 (i $) - (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropyl-methanesnlfanyl) piopionic acid (428 mg) ).

Step 3 [0212] To a mbcture of 2(ffi-(2,2,3,3,3-pentaf3uoropropy3amino)-3-(cyclopropyi-methanesulfanyl)propioric acid (150 mg, 0.49 mmol), 3(iS)-arnino-2-hydroxy-pentanoic acid cyclopropylamide hydrochloride (102 mg, 0.49 mmol), EDC (114 mg, 0.74 mmol)and HOBt (79 mg, 0.59 mmol) in dichlorrnethane was added 7Vhnethylmoipholine (0.215 mL, 1.96 mmol). The reaction nmrture was stirred for 2 h ai room iemperature and then diluted with. ethy!aceiate and washed vdih sodium bicarbonate solution. The organic layer was dried and concentrated to provide 2“hydroxy-3(.5)-[2(iJ)-(2,2,3,3,3-peniafluoiūpropylanmo)-3-(cyclopropylmethane-sulfanyl)propionyIamino]pentanoic acid cyclopropyIamide (169 mg).Step 3 To a mbcture of 2 (fi- (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropy-methanesulfanyl) propioric acid (150 mg, 0.49 mmol), 3 (iS) -arnino -2-hydroxy-pentanoic acid cyclopropylamide hydrochloride (102 mg, 0.49 mmol), EDC (114 mg, 0.74 mmol) and HOBt (79 mg, 0.59 mmol) in dichlornethane was added to 7 Vhnethylmoiphol (0.215 mL, 1.96 mmol). 2-hydroxy-3 (.5) - [2 (iJ) - (2 2,3,3,3-peniafluoro-propylanmo) -3- (cyclopropylmethane-sulfanyl) propionylamino] pentanoic acid cyclopropyIamide (169 mg).

Step 4 [0213] To an NMP solution (5 mL) of 2-hydioxy-3(jS)-[2(£)-(2,2,3,3,3-pentafinoropropyl-ammo)-3-(cyc]opropyImeĪLanesulfanyl)propionylamino]pentanoic acid cycIopropyiamide (169 mg, 0.37 mmol) was added an aaueous soluiion(5 mL) of ΟΧΟΝΕ (342 mg, 0.56 mmol). After stirring for 2 h at room iemperature mora apueous ΟΧΟΝΕ (228 mg) was added along with methanol (5 mL). After stirring for additional 2 h. ths reaction was diluted with ethylacetate and Tvashed with a sat’d brine solution. The organic layer was separated, diied and concentrated to provide a v/hite solid to which was added dichloromethane (10 mL) and Dess-Martin periodane.Step 4 To An NMP Solution (5 mL) of 2-Hydroxy-3 (jS) - [2 (E) - (2,2,3,3,3-pentafinoropropyl-ammo) -3- (cyc) opropylamide lanesulfanyl) propionylamino] pentanoic acid cyclopropyl amide (169 mg, 0.37 mmol) was added as a solid (5 mL) of ΟΧΟΝΕ (342 mg, 0.56 mmol). After stirring for 2 h at room temperature (228 mg) was added along with methanol (5 mL). After stirring for additional 2 h. ths reaction was diluted with ethylacetate and Tvashed with a sat'd brine solution. Dichloromethane (10 mL) and Dess-Martin periodic.

To this Leterogeneous rnixture wss added acetonitrile (3 mL) ibllowed by NMP (6 mL) which . provided a homogeneous reaction. After 5 h, the reaction was diluted vviih ethylacetate and washed with sodīum bicarbonate solution. The organic layer was dried and concentrated to provide the crude product as a white solid. To this vfhite solid was added ethanol and the mbcture was heated to reflux. The stili heterogeneous mixture was allovred to cool to room iemperature and was filtered to provide the title compound as a white solid (115 mg). M. pt 196.1-196.7 DC.This is Leterogeneous rnixture wss added to acetonitrile (3 mL) ibllowed by NMP (6 mL) which. provided a homogeneous reaction. After 5 h, the reaction was diluted with vinyl bicarbonate solution. The organic layer was dried and concentrated. To this vfhite solid was added ethanol and the mbcture was heated to reflux. The style of the heterogeneous mixture was allovred to 115%. M. pt 196.1-196.7 DC.

[0214] Proceeding as above the following compounds were prepared: . A-cyclopropyl-3ri-{3-he]izenesulfonyl-2ū-[2,2,2-trifluoro-lX(4-fluoro-phenyl)-ethylamdno]-propionylainiQo}-2-oxo-pentanaxnide, LC-MS 558(M+H); and 77-cyc3opropyl-35'-[3-cyclopropy]methanesulfonyl-2/?-(2,2,3,3,4,4,4-heptafluoro-butylamino)-propionylamiino]-2-oxo-pentaxLaDiide, LC-MS 542(M+H). 71 71LV 13669 Eīample 5[0214] Proceeding as above the following compounds were prepared:. Α-cyclopropyl-3β- (3-he] isenesulfonyl-2β- [2,2,2-trifluoro-1X (4-fluoro-phenyl) -ethylamino] -propionylamino} -2-oxo-pentanxide, LC-MS 558 ( M + H); and 77-cyc3-propyl-35 '- [3-cyclopropy] methanesulfonyl-2H- (2,2,3,3,4,4,4-heptafluoro-butylamino) -propionylamino] -2-oxo-pentaxLaDide, LC- MS 542 (M + H). 71 71LV 13669 Eleample 5

Syntheis of ΤΤογοΙορΓοργΙ-Β#- {4-meihanesulfonyl-2iS'-[2;2J2-trifluoro-liS'-(4-iluoro-phenyl)-ethylamino]-butyrylamino} -2-oxo-pentanamideSyntheis of ΤΤογοΙορΓοργΙ-Β # - {4-Methanesulfonyl-2'S '- [2; 2J2-trifluoro-1S' - (4-fluoro-phenyl) -ethylamino] -butyrylamino} -2-oxo-pentanamide

{0215] (6) Methyl 2-anWo-4-methyIsulfanylbuiyrate hydrochloride (750 mg, 3.76 mmol) and 2,2,2-trifiuoro-l-(4-fiuoro-phenyl)-eihanone (721 mg, 3.76mmoI) was dissolved inmethanol (15 mL) and ihen potassiirm carbonate (1.04 g, 7.52 mmol) was added to the solution. The mizture wss stiired at 55 °C for 23 hours and ihen concentrated to dryness on a rotovap. The residue was combined with toluene (20 mL) and the rnixture was concentrated to dxyness on a rotovap. The residue was combined \vith acetonitrile (10 mL) and the mixture v/as stirred at approximately -30 °C. Zinc borohydride, prepared by adding a 1M zinc chloiide solution in ether (5.64 mL) to a mkture of sodium borohydride (427 mg, 11.28 mmol) stirriugin ether (lOmL) and ihen stining this mixtuie 19 hours, Tvas added and the reaction stirred for approximateiy 7 honrs at reduced temperature and ihen an additionaļ 16 honrs ai room temperature. The reaction misture was quenched with 1N HC3, diiuted wiih ethyl acetate, and washed with brine (2X50mL). The organic layer was dried and concentrated to provide 2^-(2^jZ-bifluoro-l )5-(4-fluorophenyl)ethylannno]-4-methylsulf3nylbutyiic acid (1.15 g) as solid.{0215] (6) Methyl 2-anWo-4-methyIsulfanylbuiyrate hydrochloride (750 mg, 3.76 mmol) and 2,2,2-trifluoro-1- (4-fluorophenyl) ethanone (721 mg, 3.76mmoI) was dissolved inmethanol (15 mL) and potassium carbonate (1.04 g, 7.52 mmol) were added to the solution. The mizture wss stretched at 55 ° C for 23 hours and was concentrated on dryness on a rotovap. The residue was combined with toluene (20 mL) and the rnixture was concentrated to dxyness on a rotovap. The residue was combined with acetonitrile (10 mL) and the mixture was stirred at about -30 ° C. Zinc borohydride, prepared by adding a 1 M zinc chloiide solution in ether (5.64 mL) to stir the borohydride (427 mg, 11.28 mmol), stirriugin ether (lOmL) and stirring for 19 hours. approximateiy 7 honrs at reduced temperature and skin 16 hrs ai room temperature. The reaction misture was quenched with 1N HC3, and was washed with brine (2X50mL). 2- [2- (2-Fluoro-1-fluorophenyl) -5- (4-fluorophenyl) ethylannno] -4-methylsulf3nylbutyiic acid (1.15 g) as solid.

[0216] 2iS-[2,2,2-Tri:tiuoro-ll5-(4-fhiorophenyl)ethylamino]-4-me1hylsu]ianylbutyric acid (150 mg, 0.46 mmol), cyclopropyl 36ī-anhno-2-hydroxypentanamide hydrochloride (106 mg, 0.51 mmol), EDC (132 mg, 0.69 mmol) andHOBt (75 mg, 0.55 mmol) were combined in DCM (10 mL) and the mbcture was stirred at room temperature while 7V-methylmorpholme (0.253 mL, 2.3 mmol) was added. The mixture was stirred for 2 hours and 15 minūtes and then diiuted wīth ethy] acetate. The mixtnre was washed with sodium bicarbonate solution (2X35mL) and the he organic layer was dried and concentrated to provide JV-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2*5'[2,2,2-trifluoro-16’-(4-fluoro-phenyl)-eihylaxnino]-butyrylamino}-pentanamide (188 mg) as a white solid.2'S- [2,2,2-Tri: Thio-11,5- (4-fluorophenyl) ethylamino] -4-methylphenyl] ynylbutyric acid (150 mg, 0.46 mmol), cyclopropyl 36-anhno-2-hydroxypentanamide hydrochloride ( 106 mg, 0.51 mmol), EDC (132 mg, 0.69 mmol) and HOBt (75 mg, 0.55 mmol) were combined in DCM (10 mL) and the 7V-methylmorpholme (0.253 mL, 2.3 mmol) was added. was added. The mixture was mixed for 2 hours and then diiuted with ethy] acetate. The mixture was washed with sodium bicarbonate solution (2X35mL) and the organic layer was dried and concentrated to provide N-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2'-5,2,2,2-trifluoro- 16 '- (4-Fluoro-phenyl) -hexylamino] -butyrylamino} -pentanamide (188 mg) as a white solid.

[0217] Af-Cyclopropyl-2-hydroxy-3j5-{4-methanesulfonyl-2j5-[23232-trifluoro-l;5-(4-fhioro-phenvl)-ethylanimo]-butyrylarQino}-pentanarnide (188mg, 0.39mmol) was dissolved in 1- 72 methyl-2-pyrrolidinone (5 mL) and the solution was stirredat room temperaimevhile an' aqueous solution of oxone (5 mL, 434 mg, 0.71 mmol) was added. The mixture was stiired for lhour and 45 minūtes and then diluted vrith ethyl acetate. The mbcture was washed with brine (3X25mL) and the organic layer v/as dried and concentrated. The residue was dissolved in 1-methyl-2-pyīiolidinone (5 mL) and then Less-Martin (232 mg, 0.55 mmol) was added to the solution. The reaction v/as allowed to proceed for 1 hour and then the solution vvas diluted v/ith ethyl acetate. The mixture was washed νύΰι sodium bicarbonate solution (3X30mL) and ths organic layer was dried and concentrated. The residue was combine witb ether was added to the soličL The mixture v/as scraped and iiltered to provide 7V-cyclopropyl-3iS'- {4-methanesulfonyl-2^-(2,2,2-trifļuoro-liS,-(4-fluoro-phenyl)-ethylanjino]-bu!yrylainino}-2-oxo-pent£n2mide (114mg) as awhiiesoIid (mp 152.5r153.5 °C). LC-MS 510(M+H).N-Cyclopropyl-2-hydroxy-3β- {4-methanesulfonyl-2- [23232-trifluoro-1; 5- (4-fluoro-phenvl) -ethylamino] -butyryl-quino} pentanarnide (188 mg, 0.39 mmol) was dissolved in 1- 72 methyl-2-pyrrolidinone (5 mL) and the solution was added to the temperature solution of the oxone (5 mL, 434 mg, 0.71 mmol) was added. The mixture was stretched for lhour and 45 minutes and then diluted vrith ethyl acetate. The mbcture was washed with brine (3X25mL) and the organic layer was dried and concentrated. The residue was dissolved in 1-methyl-2-pyrimolidinone (5 mL) and then Less-Martin (232 mg, 0.55 mmol) was added to the solution. The reaction v / s allowed for 1 hour and then the solution was diluted v / ith ethyl acetate. The mixture was washed with sodium bicarbonate solution (3X30mL) and ths organic layer was dried and concentrated. N-cyclopropyl-3'S'- {4-methanesulfonyl-2 '- (2,2,2-trifluoro-liS, - (4)) -fluoro-phenyl) -ethylanino] -butyrylino} -2-oxo-pentanamide (114mg) as awhiiesoide (mp 152.5r153.5 ° C) LC-MS 510 (M + H).

Bioīogical Examples Esample 1Biohealthy Examples Esample 1

Cathepsin B Asssv [0218] Solutions of iest corcoounds in varying concentraticns wsre ņrepared in 10 pL of dimeihvl sulfoxide (DMSO) and .then diluted into assay buffer (40 pL, comprising: N/7-bis(2-hydroxyetiay!)-2-ammoethanesuhonic acid (BBS), 50 mM (pH 6); ņolyoxyeihyleaesorbitan monolaurate, 0.05°/o; and dithiothreitol (DTT), 2.5 miri). Human cathepsin B (0.025 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay Solutions v/ere mixed for 5-10 seconds on a shaker plate, covered and incubatsd for 30 min at room temperature. Z-FR-AMC (20 nMoles in 25 pL of assay buffer) was added to the assav Solutions and hydrolysis was fcllcv/ed spectrophotometricaIly at (λ 460 nm) for 5 min. Apparent inhibition constants (K,·) were calculated from the enzyme progress curves using Standard mathematical models.Cathepsin B Asssv Solutions of cormorants in varying concentraticns for 10 pL of dimethyl sulfate (DMSO) and .then diluted into assay buffer (40 pL, including: N / 7-bis (2-hydroxyetiay!) - 2 -ammoethanesuhonic acid (BBS), 50 mM (pH 6), monolaurate of ololyoxyeeaeaorbitan, 0.05 ° / o, and dithiothreitol (DTT), 2.5 µm). Human cathepsin B (0.025 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay solutions are mixed for 5-10 seconds at a 30 min at room temperature. Z-FR-AMC (20 nMoles in 25 pL of assay buffer) was added to the assav. Solutions and hydrolysis was fcllcv / ed spectrophotometrics (λ 460 nm) for 5 min. Apparent inhibition constants (K, ·) were calculated from the enzyme progress curves using Standard mathematical models.

[0219] Compounds of the invention were tested hy the above-described assay and observed to exhibit cathepsin B inhibitory activity. 73 73LV 13669Compounds of the invention were the above-described assay and observed to exhibit cathepsin B inhibitory activity. 73 73LV 13669

Example 2 Cathepsin KAssay [0220] Solutions of tēst compounds in varying concentrations -ivere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay Solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-Phe-Arg-AMC (4 uMoles in 25 pL of assay buffer) was added to the assay Solutions and hydrolysis was followed spectrophotometrically at (λ 460 mn) for 5 min. Apparent inhibition constants (3¾) were calculated troni the enzyme progress curves using Standard mathematical models.EXAMPLE 2 Cathepsin KAssay Solutions of the compound in varying concentrations -vere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5) mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds at a 30 min at room temperature. Z-Phe-Arg-AMC (4 µMoles in 25 pL of assay buffer) was added to the assay at (λ 460 mn) for 5 min. Apparent inhibition constants (3¾) were calculated by the standard mathematical models.

[0221] Compounds of the invention v/ere tested by the above-described assay and observed to exhibii cathepsin K inhibitory activity.Compounds of the invention v / ere body by the above-described assay and inhibited cathepsin K inhibitory activity.

Example 3'Example 3 '

Cathepsin L Assay [0222] Solutions of tēst compounds in varying concentrations tvers prepared in 10 pL of dimethy] sulfoside (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 5.5): EDTA, 2.5 mM;.and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay Solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room teioperature. Z-Phe-Arg-AMC (1 nMoles in 25 pL of assay buifer) was added to the assay Solutions and hydrolysis was foiiovved spectrophotometrically at (λ 460 rau) for 5 min. Apparent inhibition constants (K,·) were calculated from the enzyme progress curves using Standard mathematical models.Cathepsin L Assay [0222] Solutions of the Inverting Compounds of the Dosage of Dimethy] sulfoside (DMSO) and then diluted into assay buffer (40 pL, including: MES, 50 mM (pH 5.5): EDTA, 2.5 mM) .and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room teioperature. Z-Phe-Arg-AMC (1 nMoles in 25 pL of assay buifer) was added to the assay solution (λ 460 rau) for 5 min. Apparent inhibition constants (K, ·) were calculated from the enzyme progress curves using Standard mathematical models.

[0223] Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin L inhibitory activity.Compounds of the invention were described by the above-described assay and inhibited cathepsin L inhibitory activity.

Eiample 4 Cathepsin S Assay [0224] Solutions of tēst compounds in varying concentrations were prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100-mM); β-mercaptoethanol, 2.5 mM; andBSA, 0.00%. Human cathepsin S (0.05 pMoles in 25 pL of assay buffer) was added to the dilutions. 74Eiample 4 Cathepsin S Assay Solutions of the compounds of varying concentrations were prepared in 10 µL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 µL, containing: MES, 50 mM (pH 6.5); EDTA, 2.5) mM; and NaCl, 100 mM); β-mercaptoethanol, 2.5 mM; andBSA, 0.00%. Human cathepsin S (0.05 pMoles in 25 pL of assay buffer) was added to the dilutions. 74

The assay Solutions were icdxed for 5-10 seconds on a shaker plate, covered and incubated for 30 min ai room temperature. Z-Val-Val-Arg-AMC (4 nMoles in 25 pL of assay buffer containiag 10% DMSO) was added to the assay Solutions and hydrolysis was followed spectophotomstrically (ai λ 460 nm) for 5 min. Apparent inhibition constants (Kj) were calculated from the enzyme progress cuives using Standard raathematical models.The Assay Solutions were icdxed for 5-10 seconds at a 30 min ai room temperature. Z-Val-Val-Arg-AMC (4 nMoles in 25 pL of assay buffer containiag 10% DMSO) was spectophotomstrically (ai λ 460 nm) for 5 min. Apparent inhibition constants (Kj) were calculated from the enzyme progress cuives using Standard raathematical models.

[0225J Compounds of the invention were tested by the above-described assay and observed to exhibit caihepsin S inhibitory activity of &lt; or = 100 nm.[0225J Compounds of the Invention by the above-described Assay and Inhibitory Activity of &lt; or = 100 nm.

Example 5 Caihepsin F Ass ay [0226] Solutions of tēst compounds in vaiying concenirations rvere prepared in 10 uL of dimethyl sulfoxids (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCĻ 100 mM); DTT, 2.5 mM; andBSA, 0.01%. Human cathepsin F (0.1 pMoles in 25 uL of assay bufier) was added to the dilutions. The assay Solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature. Z-Phe-Arg-AMC (2 nMoles in 25 pL of assay bufier containiag 10% DMSO) was added to the assavSolutions and hydrolysis was followed spectrophoiometrically (at λ 460 nm) for 5 min. Apparent inbibition constants (Kj) were calculated from the enzvme progress curves using Standard maihematical models.Example 5 Caihepsin F Ass ay Solutions of the compound compounds of the study of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 6.5); 2.5 mM and NaCl 100 mM); DTT, 2.5 mM; andBSA, 0.01%. Human cathepsin F (0.1 pMoles in 25 uL of assay bufier) was added to the dilutions. The assay solutions were mixed for 5-10 seconds at a 30 min at room temperature. Z-Phe-Arg-AMC (2 nMoles in 25 pL of assay buffer containing 10% DMSO) was followed by spectrophoiometrically (at λ 460 nm) for 5 min. Apparent inbibition constants (Kj) were calculated from the enzyme progress curves using Standard maihematical models.

[0227] Compounds of the invention were tested by the above-described assay and observed to exhibit caĪhepsin F inhibitory aciivity.Compounds of the invention were the above-described assay and inhibitory factor inhibition.

Evample 1Evample 1

Representativepharmaceuiical foimulations Containing a Compound of Formula (I)Representativepharmaceuiical foimulations Containing a Compound of Formula (I)

ORAIFORMULATIONORAIFORMULATION

10-100 mg 105 mg 18 mg q.s. to 100 mL10-100 mg 105 mg 18 mg q.s. to 100 mL

Compound of Formula (I) Citric Acid Monohydrate Sodium Hydroxide Flavoring Water 75 75LV 13669Compound of Formula (I) Citric Acid Monohydrate Sodium Hydroxide Flavoring Water 75 75LV 13669

INTRAVENOUS FORMULATIONINTRAVENOUS FORMULATION

Compound of Formula (3) 0.1-10 mg Dextrose Monohydrate o.s. to matē isotonic Citdc Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Waier for Injection q.s. to 1.0 mL TABLETFOKMJLATION Compormd of Formula (I) 1% Microcrystaīline Cellulose 73% Stearic Acid 25% Colloidal Silica 1% [0228] The foregoing invention has been described in some detsil by way of illusiraiioa and examp3s, for pmposes of claiity asa undersianding. Ii \vill be obvious to one of sl-dll in ihe art ihat changes and modincations may be practiced within ihe scope of ihe appended claims. Therefore, ii is to be undersiood ihat ihe above description i-s intended to be illustrative and not restrictive. The scope of the invention should, therefore. be deiennined not with leference to ihe above description, but shosld issiead be detensined wiih reference to the follovdng appended claims, along wiih the full scope of eauivalents to which such claims are entitled. 1 1 LV 13669Compound of Formula (3) 0.1-10 mg Dextrose Monohydrate o.s. it is isotonic Citdc Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Waier for Injection q.s. to 1.0 mL TABLETFOKMLATION Compormd of Formula (I) 1% Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica 1% [0228] For the foregoing invention has been described in some of the cases. You can find one of the slideshows that you can use in your application. Therefore, it is to be a description of the above mentioned description. The scope of the invention should, therefore. as a matter of course, but a shosld is a detoxified wiih reference to the follovdng appended claims; 1 1 EN 13669

CLAĪMS 1. A compound ofFoimula (I):CLAIM 1. A compound ofFuloula (I):

. where: R1 is hydrogen or alkyl; R2 is cycloalkyl, cycloallcylalkyl, aralkyl, heteroaryl, or heteroaralkyl optionally substituted witb one or two substitutents mdependently selected from alkyl, alkoxy, or halo; īC is alkyl or alkoxyalkyl; . R4 is hydrogen or alkyl; or RJ and R4 together with the carbon atom to which they are attached forni cycloalkylene optionally substituted with one to four halo or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, or haloalkyl; . R5 is alkyl, haloalkyl optionally substituted with cycloālkyl. aiyl, heteroaryl, heterocycloaUcyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylaikyl, -(alķylene)-X-R9 (where X is -O-, -S-, -SO-, -S02-, -CONH-, -NHCO-, or -NHS02- and R9 is aikyl: haloaIkyl, cycloalkylalkyl, aiyl, aralkyl, heteroaryl, heteroaxalkyl, heterocycloalkyl; or heterocycloalkylalkyl), or-(alkylene)-Xl-(haloalkylene)-R10 (where X1 is -0--, -S-, -SO-, -S02-, -CONH-, -NHCO-, or -NHSO2- and R10 is cycloalkyl, aiyl, heteroaryl, or heterocycloal'kyl), wherein the aromatic or alicycļic ring in R5 is optionally substituted with one, two, or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from cyano, hydroxyalkyl, alkoxyalkyl, amirioalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyialkyl, acyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, arālkyloxycarbonyl, . heteroaryloxycarbonyl, hēteroaxalkyloxycarbonyl, heterocycloalkyloxycarbonyl, 2 cycloalkyloxycafbonyl3 aryloxy3 heteroaryloxy3 ara!kyloxy, heteroaralkyloxy, aminocarbonyl3 aminosulfonyl, or -S02Rn (where R11 is alkyl3 axyl3 heteroaryl3 or heterocycloalkyl); and . further wherein the aromatic or alicyclic ring in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl3 alkoxy, hydroxy, haloalkoxy, orhalo; .. R1 is hydrogen or alkyl; R2 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl, or heteroaralkyl optionally substituted by one or two substituents mdependently selected from alkyl, alkoxy, or halo; C is alkyl or alkoxyalkyl; . R4 is hydrogen or alkyl; or RJ and R4 together with the carbon atom to which they are attached, cycloalkylene or substituted with one to four halo or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, or haloalkyl; . R5 is alkyl, haloalkyl substituted substituted with cycloalkyl. allyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkynyl, - (allyl) -X-R9 (where X is -O-, -S-, -SO-, -SO2-, -CONH-, -NHCO-, or -NHSO 2 - and R 9 is alkyl: haloalkyl, cycloalkylalkyl, allyl, aralkyl, heteroaryl, heteroaxalkyl, heterocycloalkyl; or heterocycloalkylalkyl, or- (alkylene) -X 1 - (haloalkylene) -R 10 (wherein X 1 is -O-, - S-, -SO-, -SO2-, -CONH-, -NHCO-, or -NHSO2- and R10 is cycloalkyl, allyl, heteroaryl, or heterocycloalkyl, wherein the aromatic or alicyclic ring in R5 is optionally substituted with one, two, or three Ra selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from cyano, hydroxyalkyl, alkoxyalkyl, amirioalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,. heteroaryloxycarbonyl, heteroxyalkyloxycarbonyl, heterocycloalkyloxycarbonyl, 2 cycloalkylxycafonyl3 aryloxy3 heteroaryloxy3 arylloxy, heteroaralkyloxy, aminocarbonyl3 aminosulfonyl, or -SO2Rn (where R11 is alkyl3 axyl3 heteroaryl 13 or heterocycloalkyl); and. furthermore, selected from alkyl, haloalkyl 3 alkoxy, hydroxy, haloalkoxy, orchalo; .

Rd is haloalkyl; R7 is hydrogen or baloalkyl; andRd is haloalkyl; R7 is hydrogen or baloalkyl; and

Rs is hydrogen, alkyl, haloalkyl, cycloalkyl3 aryl, hetēroaxyls heterocycloalkyl attached via a carbon atom wherein the aromatic or alicyclic ring in Rs is optionally substituted with one3 two3 or three Re independently selected from alkyl3 halo, haloalkyl, hydroxy3 alkoxy3 haloalkoxy3 alkoxycaxbonyl3 carboxy3 cyano3 alkylsulfonyl, or aminosulfonyl; or a pharmaceutically-acceptable salts thereof. 2. The compound of Claim 1 wherein R1 is hydrogen and R2 is cyclopropyl, 1-phenylethyl, or liT-pyraz'ol-5-yl. 3. Tne compound of Claim 1 wherein R is hydrogen and R~ is cyclopropyl. 4. The compound of Claim 2 or 3 wherein RJ is hydrogen and R4 is alkyl. 5. The compound of Claim 2 or '3 wherein RJ is hydrogen and R4 is methyl, ethyl, propyl or butyl. - 6. The compound of Claim 2 or 3 wherein RJ is hydrogen and R4 ethyl. 7. The compound of Claim 2 or 3 wherein R3 and R4 are alkyl. 8. The compound of Claim 2 or 3 wherein R3 and R4 are independently methyl or ethyl. 9. The compound of Claim 2 or 3 wherein R3 and R4 are methyl. 10. The compound of Claim 2 or 3 wherein R3 and R4 together with the carbon atom to which they are attached form cycloalkylene. 3 3 LV 13669 11. The compound of Claim.2 or 3 wherein R3 and R4 together with tīne carbon atom to which they are attached foim cyclopropylene. 12. The compound of any of the Claims 2-11 wherein R is haloalkyl and R and R are hydrogen. 13. The compound of any of the Claims 2-11 wherein R6 is 2,2,2- trifluoroethyl or 1,1,2,2,2-pentafluoroethyl and R7 and R8 are hydrogen. 14. The compound of any of the Claims 2-11 wherein R6 is haIoalkyl, R7 is haloalkyl, s andR ishydrogen. ' A 7 15. The compound of any of the Claims 2-11 wherein R is haloalkyl, R is alkyl, and R8 is hydrogen. 16. The compound of any of the Claims 2-11 wherein R is haloalkyl, R is hydrogen, and R8 is aryl optionally substituted with one, two, or tliree Re. 17. The compound of any of the Claims 2-11 wherein R6 is trifhioromethyl or difiuoromethyl, R7 is hydrogen,.and R8 is 4-fluorophenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difiuorophenyl. . ~ . 18. The compound of any of the Claims 2-11 wherein R is haloalkyl, R is hydrogen, and R8 and R8 is heteroaiyl optionally substituted with one,' two, or tbree Re. .19. The compound of any of the Claims 2-18 wherein R5 is cycloalkylalkyl optionalIy ' substituted with one, two, or tbree Ra independently selected from alkyl or halo or an Rc selected from aralkyl or heteroaralkyl. 20. The compound of any of the Claims 2-18 wherein R5 is 1-methylcyclopentylmethyl, 1 -methylcyclohexyl, lrmethylcyclobutyl, l-methyl-3,3-difluorocyclobutyfrnethyl, l-methyl-4,4-difluorocyclohexylmethyl, Tberrzyl-cyclopropylmethyl, Tthiazol-2-ylmethylcyclopropyl-methyl, or i-methyl-3,3-difluorocyclopentylmethyl.Rs also hydrogen, alkyl, haloalkyl, cycloalkyl3 aryl, heteroaxyls heterocycloalkyl attached to the carbon atom aromatic or alicyclic ring in Rs is also substituted with one3 two or three Re and selected from alkyl3 halo, haloalkyl, hydroxy3 alkoxy3 haloalkoxy3 alkoxycaxbonyl3 carboxy3 cyano3 alkylsulfonyl , or aminosulfonyl; or aery-acceptable salts. 2. The compound of Claim 1 wherein R1 is hydrogen and R2 is cyclopropyl, 1-phenylethyl, or liT-pyrazol-5-yl. 3. The compound of Claim 1 is hydrogen and R 1 is cyclopropyl. 4. The compound of Claim 2 or 3 is hydrogen and R4 is alkyl. 5. The compound of Claim 2 or 3 is hydrogen and R4 is methyl, ethyl, propyl or butyl. - 6. The compound of Claim 2 or 3 RJ is hydrogen and R4 ethyl. 7. The compound of Claim 2 or 3 is R3 and R4 are alkyl. 8. The compound of Claim 2 or 3 is methyl or ethyl. 9. The compound of Claim 2 or 3 is R3 and R4 are methyl. 10. The compound of Claim 2 or 3 is R3 and R4 together with the carbon atom which they are attached form cycloalkylene. 3 3 EN 13669 11. The compound of Claim.2 or 3, R3 and R4 together with the carbon atoms which they are attached to the main cyclopropylene. 12. The compound of any of the Claims 2-11 R is haloalkyl and R and R are hydrogen. 13. The compound of any of the Claims 2-11, R6 is 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl and R7 and R8 are hydrogen. 14. The compound of any of the Claims 2-11, wherein R6 is haloalkyl, R7 is haloalkyl, s andR ishydrogen. A 7 15. The compound of any of the Claims 2-11 wherein R is haloalkyl, R is alkyl, and R 8 is hydrogen. 16. The compound of any of the Claims 2-11 R is haloalkyl, R is hydrogen, and R8 is aryl optionally substituted with one, two, or tliree Re. 17. The compound of any of the Claims 2-11, R6 is trifluoromethyl or difluoromethyl, R7 is hydrogen, and R8 is 4-fluorophenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluoro-phenyl. . ~. 18. The compound of any of the Claims 2-11 R is haloalkyl, R is hydrogen, and R8 and R8 are heteroaryl optionally substituted with one, 'two, or tbree Re. .19. The compound of any of the Claims 2-18 and R5 is cycloalkylalkyl optionally substituted with one, two, or one or more of selected from aralkyl or heteroaralkyl. 20. The compound of any of the Claims 2-18, R5 is 1-methylcyclopentylmethyl, 1-methylcyclohexyl, lrmethylcyclobutyl, 1-methyl-3,3-difluorocyclobutylmethyl, 1-methyl-4,4-difluorocyclohexylmethyl, Tberrzyl-cyclopropylmethyl, Tthiazol -2-ylmethylcyclopropyl-methyl, or i-methyl-3,3-difluorocyclopentylmethyl.

4 21. The compound of any of tlie Clahns 2-18 wherein R5 is alkyl. 22. The compound of 311)/- of the Claims 2-18 wherein R3 is haloalkyl substituted v/ith aryl, heteroaryl or heterocycloalkyl. 23. The compound of any of the Claims 2-18 wherein R5 is 2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difIuoro-3-morpholin-l-ylpropyl, 2,2-difluoro-3-pyridm-2-ylpropyl., 2,2-difluoro-3-pyiidiū-3-ylpropyl, or2,2-dichloro-3-phenylpropyl. 24. The compound of any of the Claims 2-18 wherein R3 is -(alkylene)-S(0)?-R9 whereR9isalkyl. 25. The compound of any of the Claims 2-18 wherein R5 is meihylsulfonylmethyl, ethylsulfonylniethyl, propyl-l-sulfonylmethyl, 2-methylpropy3sulfonyl-methyl, 2-methysulfonylethyl, or 2-ethylsulfonylethyl. 26. The compound of any of the Claims 2-18 wherein R3 is -(allcylene)-S(0)2-R9 where R9 is is aiyl or aralkyl optionallv substituted with one, two, or three Ra independentlv selected from alkyl, haloaIkyl..alkoxy. hydroxy, haloalkoxv, cyano, or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl. aryl, heteroaryl, aralkyl, heteroaralkyl3 cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycafbonyl, heteroar'alkyloxycarbonyl, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or -SO2R11 (where R11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo. 27. The compound of any of the Claims 2-18 wherein R5 is 2- difluoromethoxyphenyl-methanesulfonylmetliyl, 2-phenylsulfonylethyl, 4- fluorophenylmethanesulfonylmethyl, 4-ammocarbonylphenyhnethanesulfonyhnethyl, 4- piperazin-1-ylphehylmetlianesulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-flporoplienylinethanesulfohyhnethyl, 2,4,6-trifluorophenyhnethaīiesulfonylmethyl, 2-, 3-, or .. 5 5 LV 13669 4- Īrifluoromethylphenybnethanesulfonyl-rnethyl3 phenyhnethanesulfonyhnethyl3 2-(2-, 3-, or 4- trifluoromethylphenyl)sulfonylethy], phenyhnethanesulfonyhnethyl3 or 2-(2-, 3-, or 4- fiuorophenyl)sulfonyleihyl. 28. The compound of any of the Glaims 2-18 wherein R5 is -(alkylene)-S(0)r R9 where R9 is heteroaryl or heteroaralkyl optionally substituted with one, two3.or three Ra independently selected from alkyl3 hāloalkyl3 alkoxy3hydroxy3 haloalkoxy3 cyano3 orhalo; or optionally substituted with one ortwo Rb independently selected from hydrogen3 alkyl3 haloalkyl3 alkoxy3 hydroxy3 haloaIkoxy3 halo, carboxy3 or alkoxycarbonyl and one Rc selected from hydroxyaIkyl3 alkoxyalkyl3 aminoalkyl, aryl3 heteroaiyl3 aralkyl, heteroaralkyl, cycloaIkyl3 cycloalkyIaikyl3 heterocycloalkyl3 heterocycIoalkylalkyl3 acyl3 alkoxycarbonyl3 aiyloxycarbonyl3 aralkyloxycarbonyl3 beteroaxyloxycaibonyl3 heteroaralkyloxycarbonyl3 aryloxy. heteroaiyloxy3 aralkyloxy3 heteroaralkyloxy, aminocarbonyl, aminosulfonyl3 or -SO2R11 (whereRn is alkyl3 aiyl3 heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in Rc is optionally substituted with one3 two3 or three Rd iiidependently selected from alkyl3 haloalkyl3-alkoxy3 hydroxy3 haloalkoxy, orhalo. 29. The compound of any of the Claims 2-18 wherein R3 is pyridin-2-ylmethanesulfonyTmethyl3 pyridin-3-ylmethanesulfonylmethyl, pyridiii-4-ylmethanesulfonylmethyl, 3 -difluoro-methoxypyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxypyridin-3-imeihane-sulfonyltnethyl3 4-difluoromethoxypyridin-3-ylmethanesulfonylraethyl, 3-difluoromethoxy-pyridin-4-ylmethanesu3fonylmethyl3 pyrimidin-2-ylmethaneshlfonylmethyl3 pyrimidin-5 -yhnethanesulfonyhnethyl3 3 -trifluoromethylpyridin- 2- yhnethanesulfohyhnethyl, 4-trifiuoromethylpyridin-3-yhnethanesulfdriylmethyl3 3,5-dimethyhsoxazol-4-yhnethane-sulfonyhnēthyl, 2-fiuoroforan-5-ynuethanesulfonyhnethyl, 2-methylthiazol-4-ylmethane-sulfonylraetkyl, furan-2-yimethanesulfonyhnethyl3 2-pyridin-2-ylethanesulfonyhnethyl, 2-pyridin-3 -ylethanesulfonylmethyl,' 2-pyridin-4-ylethanesulfonylmethyl, 2-pyridin-3-yl-sulfonylethyl, 2-pyridin-4-ylsulfonylethyl3 3-pyridin- 3- ylsulfonylpropyl, l3335-triazin-2-yl-methanesulfonylmetliyl3 l,3,4-thiadiazol-2-ylmethanesulfonylmetiiyl3 oxazol-5-yl-methanesulfonylmethyl, thiazol-5-ylmethane-sulfonyhnethyl3 or thiazol-2-yhnethane-sulfonylmethyl. . 30. The compound of any of the Claims 2-18 wherein R5 is ~(alkylene)-S(0)2- R9 where R9 is cycloalkylalkyl. 6 31. The compound of any of the Claims 2-18 wherein R5 is cyclopropyImethanesulfonylmethyl. 32. A phannaceutical composition comprising a compound of any of the Claims 1-31 in admixture with one or more suitable excipients. 33. Use of a phannaceutical composition comprising a compound of any of the Claims 1-31 in admixture with one or more suitable excipients for treating a disease in an animal meaiated by Cathepsin S by administration of it to the animal. 34. Use of a compound of Claim 31 for treating a disease, wherein the disease is rheumatoid arthritis, rnultiple sclerosis, myasthema grāvis, psoriasis, pemphigus vulgaris, . Gravēs' disease, myasthenia grāvis, systemic lupus exytliemotasus, asthma, pain, and atherosclerosis 35. Use of a compound of any of Claims 1 -31 in therapy by administration of it to the patient, wherein the therapy causes an immune response in the patient. 36. The compound of Claim 1 wherein: RJ is alkyl and R4 is alkyl. 37. The compound of Claim 1 vvherein: RJ and R4 together with the carbon atom to which they are attached fonu cycloallcylene. . 3 8.-The compound of Claim 1 wherein: R3 and R4 together witli the carbon atom to which they are attached forrn piperidin-4-yl substituted at the nitrogen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or l,l-dioxotetrahydrothiopyran-4-yl. 39. The compound of Claim 1 vvherein: R6 is haloalkyl and R7 and R8 are hydrogen. V 40. The'compound of Claim 1 wherein: .. R6 is haloalkyl, R7 is haloalkyl, and Rs are hydrogen. . 7 7 LV 13669 41. The compound of Claim 1 wherein: R6 is haloalkyl, R7 is alkyl, and R8 are hydrogen. 42. The compound of Claim 1 wherein: R1 is hydrogen, R2 is cycIopropyl3 R3 is hydrogen, R4 is ethyl3 R5 is 2-methylsulfonylethyl3 R6 is trifluoromethyl, R7 is hydrogen and Rs is 4-fluorophenyl, iiamely jy-cyclopropyl-3-{4-methanesulfonyl-2-[23232-trifluoro-1 -(4-fluoro-phenyl)-ethylaminoJ- butyiylamino } -2-oxo-pentanamide. 43. The compound- of Claim 42 which is iV-cyclopropyl-3)y- {4- methanesulfonyl-2T-[2,2,2-trifluoro-· lR-(4-fluoro-phenyl)-ethylamino]-butyrylamino} -2-oxo-pentanamide. 44. The compound of Claim 1 wherein: R1 is hydrogen3 R2 is cyclopropyl3 RJ is hydrogen. R4 is ethyl, R5 is 2- f\ 7 p phenylsulfonylmethyl3 R is trifluoromethyl; R is hydrogen and R is 4-fluorophenyL namely iV’-cyclopropyl-3-{3-benzenesulfonyl-2-[2J2J2-trifluoro-l-(4-f3uoro-plienyl)-ethylamino]-propionylamino } -2-oxo-pentanamide. 45. The compound of Claim 44 which is 7V-cyclopropyl-3S- {3 - benzenesulfonyl-2R3-[2.232-trifiuoro-lT-(4-fluoro-phenyl)-eihylamiūo]-propionylamino}-2-oxo- pentanamide. 46. The compound of Claim 1 wherein: R1 is hydrogen3 R2 is cyclopropyl3 R3 is hydrogen3 R4 is efhyl, R3 is cyclopropylmethylsulforiylmethyl3 R6 is per£luoropropyl, R7 is hydrogen and Rs is hydrogen3 naxnelyJV-cycl0propyl-3-[3-cyclopropyhnethanesulfonyT2-(2,2,3,3,434:)4-heptafluoro-butyļamino)-propionylamino]-2-oxo-pentanamide. 47. The compound of Claim 46 wbich is h2-cyclopr0pyl735r-[3-cyclopropyhnethanesulfonyl-2R-(2:,2,3,334,434'heptafluoro-butylamino)-propionylamino]-2-oxo- pentanamide. . ·21. The compound of any of Clals 2-18, R5 is alkyl. 22. The compound of 311) is a haloalkyl substituted v / ith aryl, heteroaryl or heterocycloalkyl. 23. The compound of any of the Claims 2-18 is R5 is 2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholine. -ylpropyl, 2,2-difluoro-3-pyrid-2-ylpropyl, 2,2-difluoro-3-pyridoy-3-ylpropyl, or2,2-dichloro-3-phenylpropyl. 24. The compound of any of the Claims 2-18 wherein R3 is - (alkylene) -S (O)? -R9 whereR9isalkyl. 25. The compound of any of the Claims 2-18, R5 is methylsulfonylmethyl, ethylsulfonylethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methysulfonylethyl, or 2-ethylsulfonylethyl. 26. The compound of any of the Claims 2-18, R3 is - (allcylene) -S (O) 2-R9 where R9 is also an arylalkyl optionally substituted with one, two, or three independently selected from alkyl, haloIkyl ..alkoxy. hydroxy, haloalkoxy, cyano, or halo; selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl. aryl, heteroaryl, aralkyl, heteroaralkyl 3 cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycafonyl, heteroarylcycloalkyl, aryloxy, heteroaryloxy, aralkylxy, heteroaralkyl, aminocarbonyl, aminosulfonyl, or -SO2R11 (where R11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo. 27. The compound of any of the Claims 2-18, R5 is 2-difluoromethoxyphenyl-methanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, 4-ammonocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethylene sulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethanesulfonylmethyl, 4,6-Trifluorophenyhnethanesulfonylmethyl, 2-, 3-, or 5 5 LV 13669 4-trifluoromethylphenylmethanesulfonylmethyl3 phenyhnethanesulfonylmethyl3 2- (2-, 3-, or 4-trifluoromethylphenyl) sulfonylethy], phenyhnethanesulfonyhnethyl3 or 2- (2- , 3-, or 4-fluorophenyl) sulfonylihyl. 28. The compound of any of the Glaims 2-18, R5 is - (alkylene) -S (O) r R9 where R9 is heteroaryl or heteroaralkyl optionally substituted with one, two or three Ra and selected from alkyl3halalkyl3 alkoxy3hydroxy3 haloalkoxy3 cyano3 orhalo; or optionally substituted with one ortwo Rb independently selected from HydroGen3 alkyl3 haloalkyl3 alkoxy3 hydroxy3 haloaIkoxy3 halo, carboxy3 or alkoxycarbonyl and one R c selected from hydroxyaIkyl3 alkoxyalkyl3 aminoalkyl, aryl3 heteroaiyl3 aralkyl, heteroaralkyl, cycloaIkyl3 cycloalkyIaikyl3 heterocycloalkyl3 heterocycIoalkylalkyl3 acyl3 alkoxycarbonyl3 aiyloxycarbonyl3 aralkyloxycarbonyl3 beteroaxyloxycaibonyl3 heteroaralkyloxycarbonyl3 aryloxy. heteroaryloxy3 aralkylxy3 heteroaralkylxy, aminocarbonyl, aminosulfonyl3 or -SO2R11 (whereRn is alkyl3 allyl3 heteroaryl, or heterocycloalkyl); and furthermore, the aromatic or alicyclic ring in Rc is optionally substituted with one of two or three haloalkyl3-alkoxy3 hydroxy3 haloalkoxy, orhalo. 29. The compound of any of the Claims 2-18 R 3 is pyridin-2-ylmethanesulfonylmethyl-pyridin-3-ylmethanesulfonylmethyl, pyridyl-4-ylmethanesulfonylmethyl, 3-difluoro-methoxy-pyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxy-pyridin-3-imidazane sulfonylmethyl3-4-difluoromethoxypyridin-3-ylmethanesulfonylethyl, 3-difluoromethoxy-pyridin-4-ylmethanesulfonylmethyl-3-pyrimidin-2-ylmethanesulfonylmethyl-pyrimidin-5-ylmethanesulfonylmethyl-3-trifluoromethyl-pyridin-2-ylmethanesulfonylmethyl-4-trifluoromethyl-pyridin-3-ylmethanesulfonyl-pyridin-3-ylmethanesulfonylmethyl] 2-fluorophenan-5-ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonyl-tetrahydro-2-ylmethanesulfonylmethyl-2-pyrimidin-2-ylmethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl; -ylethanesulfonylmethyl, 2-pyridin-3-ylsulfonylethyl, 2-pyridin-4-ylsulfonylethyl-3-pyridin-3-ylsulfonylpropyl, 1,335-triazin-2-yl-methanesulfonylmethyl-1,3,4-thiadiazol-2-ylmethane ulfonylmethyl-3-oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethane-sulfonylmethyl-3-thiazol-2-ylmethanesulfonylmethyl. . 30. The compound of any of the Claims 2-18 and R5 is also (alkylene) -S (O) 2- R9 where R9 is cycloalkylalkyl. 6 31. The compound of any of the Claims 2-18 to R5 is cyclopropyImethanesulfonylmethyl. 32. A phytaceutical composition of the Claims 1-31 in admixture with one or more suitable excipients. Use of a phytaceutical composition of the Claims 1-31 in admixture with one or more excipients for treating a disease in an animal. 34. Use of a compound of claim 31 for treating a disease, rheumatoid arthritis, rhinitis, myasthema ditch, psoriasis, pemphigus vulgaris,. Gravės' disease, myasthenia grāvis, systemic lupus exytliemus, asthma, pain, and atherosclerosis 35. Use of a compound of any type in the patient. . 36. The compound of Claim 1: RJ is alkyl and R4 is alkyl. 37. The compound of Claim 1 vvherein: RJ and R4 together with the carbon atom which they are attached to the background cycloallcylene. . 3, 8-The compound of Claim 1: R3 and R4 together with the carbon atom to which they are attached piperidin-4-yl at the nitrogen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran- 4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl. 39. The compound of Claim 1: R6 is haloalkyl and R7 and R8 are hydrogen. R 40 is haloalkyl, R 7 is haloalkyl, and R 5 are hydrogen. . The compound of Claim 1: R6 is haloalkyl, R7 is alkyl, and R8 are hydrogen. 42. The compound of Claim 1: R 1 is hydrogen, R 2 is cyclopropyl 3 R 3 is hydrogen, R 4 is ethyl 3 R 5 is 2-methylsulfonylethyl3 R 6 is trifluoromethyl, R 7 is hydrogen and R 5 is 4-fluorophenyl, i.e. cyclopropyl-3- { 4-Methanesulfonyl-2- [23232-trifluoro-1- (4-fluoro-phenyl) -ethylamino] -butynylamino} -2-oxo-pentanamide. 43. The compound of Claim 42 which is N-cyclopropyl-3) y- {4-methanesulfonyl-2T- [2,2,2-trifluoro-1R- (4-fluoro-phenyl) -ethylamino] -butyrylamine} -2-oxo-pentanamide. 44. The compound of Claim 1: R1 is hydrogen3 R2 is cyclopropyl3 RJ is hydrogen. R 4 is ethyl, R 5 is 2- {phenylsulfonylmethyl} R is trifluoromethyl; R is hydrogen and R is 4-fluorophenyL-N'-cyclopropyl-3- {3-benzenesulfonyl-2- [2R-2-trifluoro-1- (4-fluorophenyl) -ethylamino] -propionylamino} -2-oxo-pentanamide . 45. The compound of Claim 44 which is N-Cyclopropyl-3S- {3-benzenesulfonyl-2R3- [2,232-trifluoro-1T- (4-fluoro-phenyl) -ethylamino] -propionylamino} -2-oxo-pentanamide. 46. The compound of Claim 1: R1 is also hydrogen3 R2 is cyclopropyl3 R3 is hydrogen3 R4 is also ephyl, R3 is cyclopropylmethylsulfylmethyl3 R6 is also chloropropyl, R7 is hydrogen and R5 is also hydrogen3 n-cyclopropyl-3- [3-cyclopropyhnethanesulfonyT2- 2,2,3,3,434:) 4-heptafluoro-butylamino) -propionylamino] -2-oxo-pentanamide. 47. The compound of Claim 46 is 2-cyclopropyl735r- [3-cyclopropylmethanesulfonyl-2R- (2:, 2,3,334,434'heptafluoro-butylamino) -propionylamino] -2-oxo-pentanamide. . ·

AjBSTRACTAjBSTRACT

The present mvention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present īnvention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.The present invention is based on these proteases, in particular, cathepsins B, K, L, F, and is therefore useful in treating diseases mediated by these proteases. These compounds and processes for preparing them.

Claims (47)

LV 13669 Pretenzijas 1. Savienojums ar formulu (I): e6Claims 1. A compound of formula (I): e6 kur: R1 ir ūdeņraža atoms vai alkilgrupa; R~ ir cikloalkilgrupa, cikloalkilalkilgrupa, aralkilgrupa, heteroarilgrupa vai heteroaralkilgrupa, • kas neobligāti ir aizvietota ar vienu vai diviem aizvietotājiem, kas ir neatkarīgi izvēlēti no alkilgrupas, alkoksigrupas vai halogēnu saturošas grupas; R3 ir alkilgrupa vai alkoksialkilgrupa; R' ir ūdeņraža atoms vai alkilgrupa; vai un R4 kopā ar oglekļa atomu, ar kuru tie ir savienoti, veido cikloalkilēnu, kas neobligāti ir aizvietota ar vienu līdz četrām halogēnu saturošām grupām vai heterocikloalkilēnu, kas neobligāti ir aizvietots ar alkilgrupu, alkoksialkil-grupu, hidroksialkilgrupu, acilgrupu, cikloalkilgrupu, cikloalkilalkilgrupu vai halogēnalkilgrupu; R5 ir alkilgrupa, halogēnalkilgrupa, kas neobligāti ir aizvietota ar cikloalkilgrupu, arilgrupu, heteroarilgrupu, heterocikloalkilgrupu, cikloalkilalkilgrupu, aralkilgrupu, heteroaralkilgrupu heterocikloalkilalkilgrupu, -(aIkilēn)-X-R9 (kur X ir -0-, -S-, -SO-, -SO2-, -CONH-, -NHCO- vai -NHSO2- un R9 ir alkilgrupa, halogēnalkilgrupa, cikloalkilalkilgrupa, arilgrupa, aralkilgrupa, heteroarilgrupa, heieroaralkilgrupa, heterocikloalkilgrupa vai heterocikloalkilalkilgrupa) vai -(alkilēnj-^-thalogēnalkilēnj-R10 (kur X1 ir -O-, -S-, -SO-, -S02-, -CONH-, -NHCO- vai -NHSO2- un R10 ir cikloalkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa), kur R3 aromātiskais vai alicikliskais gredzens neobligāti ir aizvietots ar vienu, divām vai trīs Ra, kas ir neatkarīgi izvēlētas no alkilgrupas, halogēnalkilgrupas, alkoksigrupas, hidroksigrupas, halogēnalkoksigrupas, ciāngrupas vai halogēnu saturošas grupas; vai neobligāti ir aizvietotas ar vienu vai divām R , kas ir neatkarīgi izvēlētas no ūdeņraža atoma, alkilgrupas, halogēnalkilgrupas, hidroksigrupas, halogēnalkoksigrupas, halogēnu saturošas grupas, karboksigrupas vai alkoksikarbonilgrupas, un vienu Rc, kas ir izvēlēts no ciāngrupas, •hidroksialkilgrupas, alkoksialkilgrupas, aminoalkilgrupas, arilgrupas, heteroarilgrupas, aralkilgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgiūpas, heterocikloalkilgrupas, heterociklo-alkilalkilgrupas, acilgrupas, arilalkilgrupas, alkoksikarbonilgrupas, ariloksikarbonilgiupas, aralkiloksikarbomlgrupas, heteroariloksikarbonilgiupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, cikloalkiloksikarbomlgrupas, ariloksigrupas, heteroariloksigrupas, aralkil-oksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonil-grupas vai -SO2R11 (kur R11 ir alkilgmpa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa); un, tālāk, kur Rc aromātiskais vai alicikliskais gredzens neobligāti it aizvietots ar vienu, divām vai trīs Rd, kas neatkarīgi ir izvēlētas no alkilgrupas, halogēnalkilgrupas, alkoksigrupa, hidroksigrupas, halogēnalkoksigrupas vai halogēnu saturošas grupas; 2 R6 ir halogēnalkilgrupa; R7 ir ūdeņraža atoms vai halogēnalkilgrupa; un Rs ir ūdeņraža atoms, allcilgrupa, halogēnalkilgrupa, cikloalkilgrupa, arilgrupa, heteroarilgrupa, heterocikloalkilgrupa, kas ir pievienota caur oglekļa atomu, kur Rs aromātiskais vai alicikliskais gredzens neobligāti ir aizvietots ar vienu, divām vai trīs Re, kas neatkarīgi ir izvēlētas no alkilgrupas, halogēnu saturošas grupas, halogēnalkilgrupas, hidroksigrupas, alkoksigrupas, halogēnalkoksigrupas, alkoksikarbonilgrupas, karboksigrupas, ciāngrupas, alkilsulfonilgmpas vai aminosulfonilgrupas; vai tā farmaceitiski pieņemami sāļi. 1 9wherein: R 1 is hydrogen or alkyl; R 1 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl or heteroaralkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy or halogen-containing; R3 is alkyl or alkoxyalkyl; R 'is hydrogen or alkyl; or and R4 together with the carbon atom to which they are attached form cycloalkylene optionally substituted with one to four halogen-containing groups or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl or cycloalkyl; haloalkyl; R5 is alkyl, haloalkyl optionally substituted with cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, - (alkyl) -X-R9 (wherein X is -O-, -S-, -SO-, -SO 2 -, -CONH-, -NHCO- or -NHSO 2 - and R 9 is alkyl, haloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, hexoalkyl, heterocycloalkyl or heterocycloalkylalkyl) or - (alkylene - th- thalogenalkylene-R 10 (wherein X 1 is -O-, -S-, -SO-, -SO 2 -, -CONH-, -NHCO- or -NHSO 2 - and R 10 is cycloalkyl, aryl, heteroaryl or heterocycloalkyl) wherein R 3 is an aromatic or alicyclic ring optionally substituted with one , two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halogen, or optionally substituted with one or two of R regardless selected from hydrogen, alkyl, haloalkyl, hydroxy, haloalkoxy, halogen-containing group, carboxy or alkoxycarbonyl and one R c selected from cyano, • hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cikloalkilalkilgiūpas , heterocycloalkyl, heterocyclo alkilalkilgrupas, acyl, arylalkyl, alkoxycarbonyl, ariloksikarbonilgiupas, aralkiloksikarbomlgrupas, heteroariloksikarbonilgiupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, cikloalkiloksikarbomlgrupas, aryloxy, heteroaryloxy, aralkyl-oxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or a group -SO2R11 (wherein R11 is alkilgmpa, aryl , heteroaryl or heterocycloalkyl); and further, wherein the Rc aromatic or alicyclic ring is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen-containing groups; 2 R 6 is haloalkyl; R7 is hydrogen or haloalkyl; and R8 is hydrogen, allyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl attached through a carbon atom, wherein the R5 aromatic or alicyclic ring is optionally substituted with one, two or three Re independently selected from alkyl, halogen containing groups, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl or aminosulfonyl; or a pharmaceutically acceptable salt thereof. 1 9 2. Savienojums saskaņā ar 1 .pretenziju, kur R ir ūdeņraža atoms un R&quot; ir ciklopropilgrupa, 1-feniletilgrupa vai lii-pirazol-5-ilgrupa.The compound of claim 1, wherein R is hydrogen and R &quot; is cyclopropyl, 1-phenylethyl or li-pyrazol-5-yl. '3. Savienojums saskaņā ar 1 .pretenziju, kur R ir ūdeņraža atoms un R ir ciklopropilgrupa.'3. The compound of claim 1, wherein R is hydrogen and R is cyclopropyl. 4. Savienojums saskaņā ar 2.vai 3 .pretenziju, kur R3 ir ūdeņraža atoms un R4 ir alkilgrupa.A compound according to claim 2 or 3, wherein R 3 is hydrogen and R 4 is alkyl. 5. Savienojums saskaņā ar 2.vai 3.pretenziju, kur RJ ir ūdeņraža atoms un R4 ir metilgrupa, etilgrupa, propilgrupa vai butilgrupa.A compound according to claim 2 or 3, wherein RJ is hydrogen and R4 is methyl, ethyl, propyl or butyl. 6. Savienojums saskaņā ar 2. vai 3.pretenziju, kur R3 ir ūdeņraža atoms un R4 ir etilgrupa.A compound according to claim 2 or 3, wherein R 3 is hydrogen and R 4 is ethyl. 7. Savienojums saskaņā ar 2. vai 3.pretenziju, kur R3 un R4 ir alkilgrupa.A compound according to claim 2 or 3, wherein R 3 and R 4 are alkyl. S. Savienojums saskaņā ar 2. vai 3.pretenziju, kur R3 un R4 ir neatkarīgi metilgrupa vai etilgrupa.The compound of claim 2 or 3, wherein R 3 and R 4 are independently methyl or ethyl. 9. Savienojums saskaņā ar 2. vai 3.pretenziju, kur R3 un R4 ir metilgrupa.A compound according to claim 2 or 3, wherein R 3 and R 4 are methyl. 10. Savienojums saskaņā ar 2. vai 3.pretenziju, kur RJ un R4 kopā ar oglekļa atomu, ar ko tās ir savienotas, veido cikloalkilēngrupuzA compound according to claim 2 or 3, wherein RJ and R4 together with the carbon atom to which they are attached form a cycloalkylene group. 11. Savienojums saskaņā ar 2. vai 3.pretenziju, kur R3 un R4 kopā ar oglekļa atomu, ar ko tās ir savienotas, veido ciklopropilēnu.A compound according to claim 2 or 3, wherein R3 and R4 together with the carbon atom to which they are attached form cyclopropylene. 12. Savienojums saskaņā ar j ebkuru pretenziju no 2.-11kur R6 ir halogēnalkilgrupa un R7 un R8 ir ūdeņraža atoms.A compound according to any one of claims 2 to 11 wherein R 6 is haloalkyl and R 7 and R 8 are hydrogen. 13. Savienojums saskaņā ar jebkuru pretenziju no 2.-11-, kur R6 ir 2,2,2- trifluoretilgrupa vai 1,1,2,2,2-pentafluoretilgrupa un R7 un Rs ir ūdeņraža atoms. C nA compound according to any one of claims 2 to 11-, wherein R 6 is 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl and R 7 and R 8 are hydrogen. C n 14. Savienojums saskaņā ar jebkuru pretenziju no 2.-11., kur R ir halogēnalkilgrupa, R ir halogēnalkilgrupa un R8 ir ūdeņraža atoms.A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is haloalkyl, and R 8 is hydrogen. 15. Savienojums saskaņā-ar jebkuru pretenziju no 2.-11., kur R ir halogēnalkilgrupa, R ir alkilgrupa un R8 ir ūdeņraža atoms.A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is alkyl, and R 8 is hydrogen. 16. Savienojums saskaņā ar jebkuru pretenziju no 2.-11., kur R ir halogēnalkilgrupa, R ir ūdeņraža atoms un R8 ir arilgrupa, kas neobligāti ir aizvietota ar vienu, divām vai tīs Re. 3 3 LV 13669A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is hydrogen, and R 8 is aryl optionally substituted with one, two, or a Re. 3 3 EN 13669 17. Savienojums saskaņā ar jebkuru pretenziju no 2.-11., kur R6 ir trifluoimetilgrupa vai difluonnetilgrupa, R7 ir ūdeņraža atoms un Rs ir 4-fluorfenilgrupa, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, vai 3,5- difluorfenilgrupa.A compound according to any one of claims 2 to 11, wherein R 6 is trifluoromethyl or difluoroethyl, R 7 is hydrogen and R 5 is 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6 -, 3,4, or 3,5-difluorophenyl. 18. Savienojums saskaņā ar jebkuru pretenziju no 2.-11., kur R ir halogēnalkilgrupa, R ir ūdeņraža atoms un R8 un Rs ir heteroarilgrupa, kas neobligāti ir aizvietota ar vienu, divām vai trīs Re.A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is hydrogen and R8 and R8 are heteroaryl optionally substituted with one, two or three Re. 19. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur Rs ir cikloalkilalkilgrupa, kas neobligāti ir aizvietota ar vienu, divām vai trīs Ra, kas neatkarīgi ir izvēlētas no alkilgrupas vai halogēnu saturošas grupas vai Rc, kas ir izvēlēta no aralkilgrupas vai heteroaralkilgrupas.A compound according to any one of claims 2 to 18, wherein R 5 is cycloalkylalkyl optionally substituted with one, two or three Ra independently selected from alkyl or halogen-containing or R c selected from aralkyl or heteroaralkyl. 20. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir l-metilciklopentilmetilgrupa, 1-metilcikloheksilgrapa, l-metilciklobutilgrupa, l-metil-3,3-difluorciklobutilmetilgnrpa, l-metil-4,4-difluorcikloheksilmetilgrupa, 1-benzil-ciklopropilmetilgi'upa, l-tiazol-2-ilmetilciklopropil-metilgrupa vai l-metil-3,3-difluorciklopentilmetil grupa.A compound according to any one of claims 2 to 18, wherein R 5 is 1-methylcyclopentylmethyl, 1-methylcyclohexylgrapa, 1-methylcyclobutyl, 1-methyl-3,3-difluoro-cyclobutylmethyl-methyl, 1-methyl-4,4-difluoro-cyclohexylmethyl, 1 benzyl-cyclopropylmethyl-yl, 1-thiazol-2-ylmethylcyclopropylmethyl or 1-methyl-3,3-difluoro-cyclopentylmethyl. 21. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir alkilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is alkyl. 22. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir halogēnalkilgrupa, kas aizvietota ar arilgrupu, heteroarilgrupu vai heterocikloalkilgrupu.A compound according to any one of claims 2 to 18, wherein R 5 is haloalkyl substituted with aryl, heteroaryl or heterocycloalkyl. 23. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir 2,2-aifluor-3-fenilpropilgrupa, 2,2-difluor-3-Īetrahidropirān-4-ilpropilgrupa, 2,2-difluor-3-morfolīn-l-ilpropilgrupa, 2,2-difluor-3-piridīn-2-ilpropilgrupa, 2,2-difluor-3-piridīn-3-ilpropilgrupa vai 2,2-dihlor-3-fenilpropilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is 2,2-aifluoro-3-phenylpropyl, 2,2-difluoro-3-ethrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholine -1-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylpropyl or 2,2-dichloro-3-phenylpropyl. 24. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir -(alkilēn)-S(0)2-R9, kur R9 ir alkilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is - (alkylene) -S (O) 2 -R 9, wherein R 9 is alkyl. 25. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir metilsulfonilmetilgrupa, etilsulfonilmetilgrupa, propil-l-sulfonilmetilgrupa, 2-metilpropilsulfonilmetilgrupa, 2-metilsulfoniletilgiupa vai 2-etilsulfoniletilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is methylsulfonylmethyl, ethylsulfonylmethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methylsulfonyl ethyl or 2-ethylsulfonyl ethyl. 26. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir -(aHdlēn)-S(0)2-R9, kur R9 ir arilgrupa vai aralkilgrupa, kas neobligāti ir aizvietota ar vienu, divām vai trīs Ra, kas neatkarīgi ir izvēlētas no alkilgrupas, halogēnalkilgrupas, alkoksigrupas, hidroksilgrupas, halogēnalkoksigrupas, ciāngrupas vai halogēnu saturošas grupas; vai neobligāti aizvietota ar vienu vai divām Rb, kas neatkarīgi ir izvēlētas no ūdeņraža, alkilgrupas, halogēnalkilgrupas, alkoksigrupas, hidroksigrupas, halogēnalkoksigrupas, halogēnu saturošas grupas, karboksigrupas vai alkoksikarbonilgrupas un vienu Rc, kas ir izvēlēts no hidroksialkilgrupas, alkoksialkilgrupas, aminoalkilgrupas, arilgiupas, heteroarilgrupas, aralkilgrupas, heteroaralkilgrupas, cikloalkil-grupas, cikloalkilalkilgrupas, heterocikloalkilgrupas, heterocikloalkilalkilgrupas, acilgmpas, alkoksikarbonilgrupas, aiiloksikarbonilgrupas, aralkiloksikarbonil-giupas, heteroariloksikarbonilgrūpas, heteroaralkiloksikarbonilgrupas, ariloksi-grupas, heteroariloksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgiupas, aminosulfonilgrupas vai -SChR11 (kur Rn ir alkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkilgrupa); un, tālāk, kur Rc aromātiskais vai alicikliskais gredzens neobligāti ir aizvietots ar vienu, divām vai trīs Rd, kas neatkarīgi ir izvēlētas no alkilgrupas, halogēnalkilgrupas, alkoksigrupas, hidroksigrupas, halogēnalkoksigrupas vai halogēnu saturošas grupas. 4A compound according to any one of claims 2 to 18, wherein R 5 is - (a Hdyl) -S (O) 2 -R 9, wherein R 9 is aryl or aralkyl optionally substituted with one, two or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxy or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, arylgroup, heteroaryl , aralkyl, heteroaralkyl, cycloalkyl group, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acilgmpas, alkoxycarbonyl, aiiloksikarbonilgrupas, aralkiloksikarbonil-giupas, heteroariloksikarbonilgrūpas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminokarbonilgiupas aminosulfonyl or -SChR11 (where Rn is alkyl , aryl, heteroaryl or heterocycloalkyl); and further, wherein the Rc aromatic or alicyclic ring is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen. 4 27. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir 2-difluormetoksifenil-metānsulfonilmetilgrupa, 2-fenilsulfoniletilgrupa, 4- fluorfenilmetānsulfonilmetilgrupa, 4-amokarbonilfenilmetānsulfonilmetilgrupa, 4- piperazīn-1 -ilfenihnetānsulfonilmetilgrupa, 2-fluorfenilmetānsulfonilmetil-grupa, 3-fluorfenilmetānsulfoniletilgrupa, 2,4,6-trifluorfenilmetānsulfonihnetil-grupa, 2-, 3- vai 4- trifluometīlfenilmetānsulfonil-metilgrupa, fenilmetānsulfoniletils, 2-(2-, 3- vai 4- trifluonnetilfemljsulfoniletils, fenilmetān-sulfonilmetilgrupa vai 2-(2-, 3- vai 4- fīuorfeniljsulfoniletilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is 2-difluoromethoxyphenylmethanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethanesulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3 -fluorophenylmethanesulfonyl-ethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2-, 3- or 4-trifluoroethylphenylmethanesulfonylmethyl, phenylmethanesulfonyl ethyl, 2- (2-, 3- or 4-trifluoromethylphenylsulfonylethyl, phenylmethanesulfonylmethyl or 2- (2-, 3- or 4-fluorophenylsulfonyl ethyl. 28. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ή -(alkilēn)-S(0)2-R9, kur R9 ir heteroarilgrupa vai heteroaralkilgrupa, kas neobligāti ir aizvietota ar vienu, divām vai trīs Ra, kas neatkarīgi ir izvēlētas no alkilgmpas, halogēnalkilgrupas, alkoksigrupas, hidroksigrupas, halogēnalkoksigrupas, ciāngrupas vai halogēnu saturošas grupas, vai neobligāti ir aizvietotas ar vienu vai divām R°, kas neatkarīgi ir izvēlētas no ūdeņraža atoma, alkilgrupas, halogēnalkilgrupas, alkoksigrupas, hidroksigrupas, halogēnalkoksigrupas, halogēnu saturošas grupas, karboksigrupas vai alkoksikarbonila un vienas Rc, kas ir izvēlēta no hidroksialkilgrupas, alkoksialkilgrupas, aminoalkilgrupas, arilgrupas, heteroarilgmpas, aralkilgrupas, heteroaralkilgrupas, cikloalkilgrupas, cikloalkilalkilgrupas, heterocikloalkilgrupas, heterociklo-alkilalkilgrupas, acilgrupas, alkoksikarbonilgrupas, ariloksikarbonilgrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksi-karbonilgrupas, ariloksigrupas, heteroariloksigrupas, aralkiloksigrupas, heteroaralkiloksigrupas, aminokarbonilgrupas, aminosulfonilgrupas vai -S02Rn (kur R11 ir alkilgrupa, arilgrupa, heteroarilgrupa vai heterocikloalkil-grupa); un, tālāk, kur Rc aromātiskais vai alicikliskais gredzens neobligāti ir aizvietots ar vienu, divām vai trīs Rd, kas neatkarīgi ir izvēlētas no alkilgrupas, halogēnalkilgrupas, alkoksigrupas, hidroksigrupas, halogēnalkoksigrupas vai halogēnu saturošas grupas.A compound according to any one of claims 2 to 18, wherein R5 is - (alkylene) -S (O) 2-R9, wherein R9 is heteroaryl or heteroaralkyl optionally substituted with one, two or three Ra, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halogen, or optionally substituted with one or two R10 independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, halogen containing group, carboxy or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroarilgmpas, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocyclo alkilalkilgrupas, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkyloxy-carbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -SO2Rn (wherein R11 is alkyl, aryl, heteroaryl or heterocycloalkyl); and further, wherein the Rc aromatic or alicyclic ring is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen. 29. Savienojums saskaņā ar'jebkuru pretenziju no 2.-18., kur R3 ir piridīh-2- ilmetānsulfonil-metilgrupa, piridm-3-ilmetāīisulfonilmetilgrupa, piridm-4-ilmetānsulfonilmetilgrupa, 3-difluor-metoksipiridīn-2-ilmetānsulfonilmetilgrupa, 2-diiluormetoksipiridīn-3-ilmetān-sulfonilmetilgrupa. 4-difluormetoksipiridīn-3-ilmetānsulfonilmetilgrupa, 3-difluoimetoksi-piridīh-4-ilmetānsulfomlmetīlgmpa,'pMmidīii-2-ilmetānsulf0nilmetilgrupa,pirimidm-5-ilmetānsulfonilmetilgrupa, 3 -trifluormetilpīridīh-2-ilmeĪānsulfonilmetilgrupa, 4-trifluormetilpiridīn-3 -ihneiānsulfonilmetilgrupa, 3,5- dimetilizoksazol-4-ilmetān-sulfonilmetilgrupa, 2-fluorfurān-5-ilmetānsulfonihnetilgrupa, 2-metiltiazol-4-ilmetānsulfonilmetil-grupa, furān-2-ilmetānsulfonilmetilgrupa, 2-piridīn-2-iletānsulfonilmetilgrupa, 2-piridm-3 -iletānsulfonilmetilgrupa, 2-piridīn-4-iletānsulfonilmetilgrupa, 2-piridīh-3 -il-sulfoniletilgrupa, 2-pixidm-4-ilsulfoniletilgrupa, 3 -piridīn-3-ilsulfonilpropilgrupa, l,3,5-triazīn-2-ilmetānsulfonilmetilgrupa, l,3,4-tiadiazol-2-ilmetānsulfonilmetilgrupa, oksazol-5-ilmetānsulfonilmetilgrupa, tiazol-5-ilmetānsulfonilmetilgrupa vai tiazol-2-ilmetānsulfonilmetilgrupa.A compound according to any one of claims 2 to 18, wherein R 3 is pyridyl-2-ylmethanesulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl, diylmethoxypyridin-3-ylmethanesulfonylmethyl. 4-Difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3-difluoro-methoxy-pyridyl-4-ylmethanesulfonylmethyl-pyrimidin-1-ylmethyl-pyrimidin-5-ylmethanesulfonylmethyl, 3-trifluoromethyl-pyridyl-2-ylmethanesulfonylmethyl, 4-trifluoromethyl-pyridin-3-ylsulfonylmethyl, 4-trifluoromethyl-pyridin-3-ylsulfonylmethyl, 3,5 - dimethylisoxazol-4-ylmethanesulfonylmethyl, 2-fluoro-furan-5-ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyrid-3-ylethanesulfonylmethyl, 2 pyridin-4-yl-ethanesulfonylmethyl, 2-pyridyl-3-ylsulfonyl-ethyl, 2-pixid-4-ylsulfonyl-ethyl, 3-pyridin-3-ylsulfonyl-propyl, 1,3,5-triazine-2-ylmethanesulfonylmethyl, 1, 3,4 thiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl or thiazol-2-ylmethanesulfonylmethyl. 30. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir -(alkilēn)-S(0)2- R9, kur R9 ir cikloalkilalkilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is - (alkylene) -S (O) 2 R 9, wherein R 9 is cycloalkylalkyl. 31. Savienojums saskaņā ar jebkuru pretenziju no 2.-18., kur R5 ir ciklopropil-metānsulfonilmetilgrupa.A compound according to any one of claims 2 to 18, wherein R 5 is cyclopropylmethanesulfonylmethyl. 32. Farmaceitiska kompozīcija, kas satur savienojumu saskaņā ar jebkuru pretenziju no 1 .-31., ar vienas vai vairāku pieņemamu pildvielu piejaukumu. 5 5 LV 13669A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, in admixture with one or more acceptable excipients. 5 5 EN 13669 33. Farmaceitiskas kompozīcijas, kas satur savienojumu saskaņā ar jebkuru pretenziju no 1.-31. ar vienas vai vairāku pieņemamu pildvielu piejaukumu, izmantošana tādas slimības ārstēšanai dzīvniekam, kur iesaistīts katepsīns S, ievadot to dzīvniekam.Pharmaceutical compositions comprising a compound according to any one of claims 1-31. the use of one or more acceptable adjuvants for the treatment of a disease in an animal involved in cathepsin S administration to an animal. 34. Savienojuma saskaņā ar 31 .pretenziju izmantošana slimības ārstēšanai, kur slimība ir reimatoids artrīts, izkliedēta skleroze, myasthenia grāvis, ņsorīāze,pemphigus vulgaris, Greiva slimība, myasthenia grāvis, sistēmiskais lupus erythemotasus, astma, sāpes un ateroskleroze.Use of a compound according to claim 31 for the treatment of a disease wherein the disease is rheumatoid arthritis, scattered sclerosis, myasthenia ditch, rhinitis, pemphigus vulgaris, Greiva disease, myasthenia ditch, systemic lupus erythematosus, asthma, pain and atherosclerosis. 35. Savienojuma saskaņā ar jebkuru pretenziju no 1.-31. izmantošana terapijā, kas izraisa imūnu atbildi pacientā, ievadot to pacientam.The compound according to any one of claims 1 to 31, according to any of claims 1 to 31 use in therapy that causes an immune response in a patient by administering it to a patient. 36. Savienojums saskaņā ar 1 .pretenziju, kur: R3 ir alkilgrupa un R4 ir alkilgrupa.The compound of claim 1, wherein: R 3 is alkyl and R 4 is alkyl. 37. Savienojums saskaņā ar 1 .pretenziju, kur: R3 un R4 kopā ar oglekļa atomu, ar ko tās ir savienotas, veido cikloalkilēnu.The compound of claim 1, wherein: R 3 and R 4 together with the carbon atom to which they are attached form cycloalkylene. 38. Savienojums saskaņā ar 1 .pretenziju, kur: RJ un R&quot; kopā ar oglekļa atomu, ar ko tās ir savienotas, veido piperidīn-4-ilgrupu, ko pie skābekļa atoma aizvieto ar etilgrupu, 2,2,2-trifluoretilgrupu vai ciklopropilgrupu, tetrahidropirān-4-ilgmpu, tetrahidrotiopirān-4-ilgrupu vai 1,1 -dioksotetrahidrotiopirān-4-ilgrupu.The compound of claim 1, wherein: RJ and R &quot; together with the carbon atom to which they are attached forms a piperidine-4-long group substituted at the oxygen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-long, tetrahydrothiopyran-4-yl or 1, 1-dioxotetrahydrothiopyran-4-yl. 39. Savienojums saskaņā ar 1 .pretenziju, kur: R6 ir halogēnalkilgrupa un R7 un Rs ir ūdeņraža atoms.The compound of claim 1, wherein: R 6 is haloalkyl and R 7 and R 5 are hydrogen. 40. Savienojums saskaņā ar 1 .pretenziju, kur: r * 7 R R ir halogēnalkilgrupa, R ir halogēnalkilgrupa un R ir ūdeņraža atoms.The compound of claim 1, wherein: r * 7 R R is haloalkyl, R is haloalkyl, and R is hydrogen. 41. Savienojums saskaņā ar 1.pretenziju, kur: R6 ir halogēnalkilgrupa, R7 ir alkilgrupa un R8 ir ūdeņraža atoms.The compound of claim 1, wherein: R 6 is haloalkyl, R 7 is alkyl, and R 8 is hydrogen. 42. Savienojums saskaņā ar 1.pretenziju, kur: R1 ir ūdeņraža atoms, R2 ir ciklopropilgrupa, R3 ir ūdeņraža atoms, R4 ir etilgrupa, R5 ir 2-metilsulfoniletilgrupa, R6 ir trifluormetilgrupa, R7 ir ūdeņraža atoms un R8 ir 4-fluorferdlgrupa, proti, Af-ciklopropil-3- {4-metānsulfonil-2-[2,2,2-trifluor-l -(4-fluor-feml)-etilamino]-butirilamino} -2-okso-pentānamīds.The compound of claim 1, wherein: R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is 2-methylsulfonyl, R 6 is trifluoromethyl, R 7 is hydrogen, and R 8 is 4-fluoro-dichloro, namely, N-cyclopropyl-3- {4-methanesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-femyl) -ethylamino] -butyrylamino} -2-oxo-pentanamide. 43. Savienojums saskaņā ar 42.pretenziju, kas iri7-ciklopropil-3R-{4-metānsulfonil-26'-[2,2,2-trifluor-lR-(4-fluor-fenil)-etilamino]- butiriIamino}-2-okso-pentānamīds. r.The compound of claim 42, which is 7-cyclopropyl-3R- {4-methanesulfonyl-26 '- [2,2,2-trifluoro-1R- (4-fluoro-phenyl) -ethylamino] -butyramine} -2 oxo-pentanamide. r. 44. Savienojums saskaņā ar 1 .pretenziju, kur: R1 ir ūdeņraža atoms, R2 ir ciklopropilgrupa, R3 ir ūdeņraža atoms, R4 ir etilgmpa, R5 ir 2-fenilsulfonilmetilgrupa, R6 ir trifluomietilgrupa, R7 ή ūdeņraža atoms un Rs ir 4-fluorfenilgrupa, proti, 77-ciklopropil-3- {3-benzenlsulfonil-2-[2,2,2-trifluor-1 -(4-fluor-feml)-etilamino]-propionilamino}-2-okso:pentānamīds.The compound of claim 1, wherein: R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is 2-phenylsulfonylmethyl, R 6 is trifluoroethyl, R 7 is hydrogen, and R 5 is 4-fluorophenyl, namely, 77-cyclopropyl-3- {3-benzenesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -ethylamino] -propionylamino} -2-oxo-pentanamide. 45. Savienojums saskaņa ar 44.pretenziju, kas ir iV-ciklopropil-3S- {3-benzenlsulfonil-2R-[2,2,2-trifluor-ld’-(4-fluor-fenil)-etilamino]-propionilamino}-2-okso-pentānamīds.45. The compound of claim 44 which is N-cyclopropyl-3S- {3-benzenesulfonyl-2R- [2,2,2-trifluoro-1 '- (4-fluoro-phenyl) -ethylamino] -propionylamino} - 2-oxo-pentanamide. 46. Savienojums saskaņā ar 1.pretenziju, kur: 6 R1 ir ūdeņraža atoms, R2 ir ciklopropilgrupa, R3 ir ūdeņraža atoms, R4 ir etilgmpa, R5 ir ciklopropilmetilsulfonilmetiigrupa, R6 ir perfhiorpropilgrupa, R7 ir ūdeņraža atoms un R8 ūdeņraža atoms, proti, JV-cildopropil-3-[3-ciklopropil-metānsulfonil-2-(2,2,3,3,4,4,4-heptafluor-butilammo)-propiomlamino]-2-okso-pentānamIds.The compound of claim 1, wherein: R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is cyclopropylmethylsulfonylmethyl, R 6 is perfluoropropyl, R 7 is hydrogen, and R 8 is hydrogen, e.g. -cyclopropyl-3- [3-cyclopropylmethanesulfonyl-2- (2,2,3,3,4,4,4-heptafluoro-butylamino) -propiomlamino] -2-oxo-pentanamide. 47. Savienojums saskaņā ar 46.pretenziju, kas ir7'/-dldopropil-3iS'-[3-ciklopropilmetānsulfonil-2i?-(2,2,3,3,4,4,4-heptafluor-butilamino)-propionilamino]-2-okso-pentānamTds.The compound of claim 46, which is 7 '-dldopropyl-3S' - [3-cyclopropylmethanesulfonyl-2-yl- (2,2,3,3,4,4,4-heptafluoro-butylamino) -propionylamino] - 2-oxo-pentanamtds.
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